Cannabis Ruderalis

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{{Short description|Class of enzymes}}
{{Short description|Class of enzymes}}
{{split|discuss=Talk:Cytochrome P450#Split proposal|date=March 2024}}
{{Pfam box
{{cs1 config|name-list-style=vanc}}{{Pfam box
| Symbol = p450
| Symbol = p450
| Name = Cytochrome P450
| Name = Cytochrome P450
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| OPM family= 39
| OPM family= 39
| OPM protein= 2bdm
| OPM protein= 2bdm
| PDB =
| CDD = cd00302
| PDB =
| Membranome superfamily= 265
| Membranome superfamily= 265
}}
}}


'''Cytochromes P450''' ('''CYPs''') are a [[Protein superfamily|superfamily]] of [[enzyme]]s containing [[heme]] as a [[cofactor (biochemistry)|cofactor]] that functions as [[monooxygenase]]s.<ref>{{cite journal | vauthors = Gonzalez FJ, Gelboin HV | title = Human cytochromes P450: evolution and cDNA-directed expression | journal = Environmental Health Perspectives | volume = 98 | pages = 81–85 | date = November 1992 | pmid = 1486867 | pmc = 1519618 | doi = 10.1289/ehp.929881 }}</ref><ref name=":0" /><ref name="pmid12369887" /> In mammals, these proteins oxidize [[steroid]]s, [[fatty acid]]s, and [[xenobiotic]]s, and are important for the [[clearance (pharmacology)|clearance]] of various compounds, as well as for hormone synthesis and breakdown. In 1963, [[Ronald W. Estabrook|Estabrook]], [[David Y. Cooper|Cooper]], and [[Otto Rosenthal|Rosenthal]] described the role of CYP as a catalyst in steroid hormone synthesis and drug metabolism. In plants, these proteins are important for the biosynthesis of [[secondary metabolite|defensive compounds]], fatty acids, and hormones.<ref name=":0">{{cite web | title = Cytochrome P450| url = http://www.ebi.ac.uk/interpro/entry/IPR001128 | work = InterPro }}</ref>
'''Cytochromes P450''' ('''P450s''' or '''CYPs''') are a [[Protein superfamily|superfamily]] of [[enzyme]]s containing [[heme]] as a [[cofactor (biochemistry)|cofactor]] that mostly, but not exclusively, function as [[monooxygenase]]s.<ref>{{cite journal | vauthors = Gonzalez FJ, Gelboin HV |author2-link=Harry Gelboin | title = Human cytochromes P450: evolution and cDNA-directed expression | journal = Environmental Health Perspectives | volume = 98 | pages = 81–85 | date = November 1992 | pmid = 1486867 | pmc = 1519618 | doi = 10.1289/ehp.929881 }}</ref><ref name=":0" /><ref name="pmid12369887" /> In mammals, these proteins oxidize [[steroid]]s, [[fatty acid]]s, and [[xenobiotic]]s, and are important for the [[clearance (pharmacology)|clearance]] of various compounds, as well as for hormone synthesis and breakdown, steroid hormone synthesis, drug metabolism, and the biosynthesis of [[secondary metabolite|defensive compounds]], fatty acids, and hormones.<ref name=":0">{{cite web | title = Cytochrome P450| url = http://www.ebi.ac.uk/interpro/entry/IPR001128 | work = InterPro }}</ref> CYP450 enzymes convert xenobiotics into hydrophilic derivatives, which are more readily excreted. In almost all of the transformations that they catalyze, P450's affect [[hydroxylation]].


CYP enzymes have been identified in all [[kingdom (biology)|kingdom]]s of life: [[animal]]s, [[plant]]s, [[fungus|fungi]], [[protist]]s, [[bacteria]], and [[archaea]], as well as in [[virus]]es.<ref>{{cite journal | vauthors = Lamb DC, Lei L, Warrilow AG, Lepesheva GI, Mullins JG, Waterman MR, Kelly SL | title = The first virally encoded cytochrome p450 | journal = Journal of Virology | volume = 83 | issue = 16 | pages = 8266–8269 | date = August 2009 | pmid = 19515774 | pmc = 2715754 | doi = 10.1128/JVI.00289-09 }}</ref> However, they are not omnipresent; for example, they have not been found in ''[[Escherichia coli]]''.<ref name="pmid12369887">{{cite journal | vauthors = Danielson PB | title = The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans | journal = Current Drug Metabolism | volume = 3 | issue = 6 | pages = 561–597 | date = December 2002 | pmid = 12369887 | doi = 10.2174/1389200023337054 }}</ref><ref name="isbn0-470-01672-8">{{cite book | vauthors = Sigel A, Sigel H, Sigel RK | title = The Ubiquitous Roles of Cytochrome P450 Proteins: Metal Ions in Life Sciences | publisher = Wiley | location = New York | year = 2007 | isbn = 978-0-470-01672-5 }}</ref> {{as of|2018}}, more than 300,000 distinct CYP proteins are known.<ref>{{cite journal | vauthors = Nelson DR | title = Cytochrome P450 diversity in the tree of life | journal = Biochimica et Biophysica Acta. Proteins and Proteomics | volume = 1866 | issue = 1 | pages = 141–154 | date = January 2018 | pmid = 28502748 | pmc = 5681887 | doi = 10.1016/j.bbapap.2017.05.003 }}</ref><ref name="urlCytochrome P450 Homepage">{{cite journal | vauthors = Nelson DR | title = The cytochrome p450 homepage | journal = Human Genomics | volume = 4 | issue = 1 | pages = 59–65 | date = October 2009 | pmid = 19951895 | pmc = 3500189 | doi = 10.1186/1479-7364-4-1-59 | publisher = University of Tennessee }}</ref>
P450 enzymes have been identified in all [[kingdom (biology)|kingdom]]s of life: [[animal]]s, [[plant]]s, [[fungus|fungi]], [[protist]]s, [[bacteria]], and [[archaea]], as well as in [[virus]]es.<ref>{{cite journal | vauthors = Lamb DC, Lei L, Warrilow AG, Lepesheva GI, Mullins JG, Waterman MR, Kelly SL | title = The first virally encoded cytochrome p450 | journal = Journal of Virology | volume = 83 | issue = 16 | pages = 8266–8269 | date = August 2009 | pmid = 19515774 | pmc = 2715754 | doi = 10.1128/JVI.00289-09 }}</ref> However, they are not omnipresent; for example, they have not been found in ''[[Escherichia coli]]''.<ref name="pmid12369887">{{cite journal | vauthors = Danielson PB | title = The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans | journal = Current Drug Metabolism | volume = 3 | issue = 6 | pages = 561–597 | date = December 2002 | pmid = 12369887 | doi = 10.2174/1389200023337054 }}</ref><ref name="isbn0-470-01672-8">{{cite book | vauthors = Sigel A, Sigel H, Sigel RK | title = The Ubiquitous Roles of Cytochrome P450 Proteins: Metal Ions in Life Sciences | publisher = Wiley | location = New York | year = 2007 | isbn = 978-0-470-01672-5 }}</ref> {{as of|2018}}, more than 300,000 distinct CYP proteins are known.<ref>{{cite journal | vauthors = Nelson DR | title = Cytochrome P450 diversity in the tree of life | journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics | volume = 1866 | issue = 1 | pages = 141–154 | date = January 2018 | pmid = 28502748 | pmc = 5681887 | doi = 10.1016/j.bbapap.2017.05.003 }}</ref><ref name="urlCytochrome P450 Homepage">{{cite journal | vauthors = Nelson DR | title = The cytochrome p450 homepage | journal = Human Genomics | volume = 4 | issue = 1 | pages = 59–65 | date = October 2009 | pmid = 19951895 | pmc = 3500189 | doi = 10.1186/1479-7364-4-1-59 | publisher = University of Tennessee | doi-access = free }}</ref>


CYPs are, in general, the terminal oxidase enzymes in [[electron transfer]] chains, broadly categorized as [[P450-containing systems]]. The term "P450" is derived from the [[spectrophotometry|spectrophotometric]] peak at the [[wavelength]] of the [[absorption spectroscopy|absorption maximum]] of the enzyme (450&nbsp;[[nanometre|nm]]) when it is in the [[redox|reduced]] state and complexed with [[carbon monoxide]]. Most CYPs require a protein partner to deliver one or more [[electron]]s to reduce the [[iron]] (and eventually molecular [[oxygen]]).
P450s are, in general, the terminal oxidase enzymes in [[electron transfer]] chains, broadly categorized as [[P450-containing systems]]. The term "P450" is derived from the [[spectrophotometry|spectrophotometric]] peak at the [[wavelength]] of the [[absorption spectroscopy|absorption maximum]] of the enzyme (450&nbsp;[[nanometre|nm]]) when it is in the [[redox|reduced]] state and complexed with [[carbon monoxide]]. Most P450s require a protein partner to deliver one or more [[electron]]s to reduce the [[iron]] (and eventually molecular [[oxygen]]).


==Nomenclature==
==Nomenclature==
[[Gene]]s encoding CYP enzymes, and the enzymes themselves, are designated with the [[gene nomenclature#Symbol and name|root symbol]] '''CYP''' for the [[protein superfamily|superfamily]], followed by a number indicating the [[gene family]], a capital letter indicating the subfamily, and another numeral for the individual gene. The convention is to ''[[Italic type|italicise]]'' the name when referring to the gene. For example, ''CYP2E1'' is the gene that encodes the enzyme [[CYP2E1]]—one of the enzymes involved in [[paracetamol]] (acetaminophen) metabolism. The '''CYP''' nomenclature is the official naming convention, although occasionally '''CYP450''' or '''CYP<sub>450</sub>''' is used synonymously. However, some gene or enzyme names for CYPs may differ from this nomenclature, denoting the catalytic activity and the name of the compound used as substrate. Examples include [[CYP5A1]], [[thromboxane]] A<sub>2</sub> synthase, abbreviated to [[Thromboxane-A synthase|TBXAS1]] ('''T'''hrom'''B'''o'''X'''ane '''A'''<sub>2</sub> '''S'''ynthase '''1'''), and [[CYP51A1]], lanosterol 14-α-demethylase, sometimes unofficially abbreviated to LDM according to its substrate ('''L'''anosterol) and activity ('''D'''e'''M'''ethylation).<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&id=3915660
[[Gene]]s encoding P450 enzymes, and the enzymes themselves, are designated with the [[gene nomenclature#Symbol and name|root symbol]] '''CYP''' for the [[protein superfamily|superfamily]], followed by a number indicating the [[gene family]], a capital letter indicating the subfamily, and another numeral for the individual gene. The convention is to ''[[Italic type|italicise]]'' the name when referring to the gene. For example, ''CYP2E1'' is the gene that encodes the enzyme [[CYP2E1]]—one of the enzymes involved in [[paracetamol]] (acetaminophen) metabolism. The '''CYP''' nomenclature is the official naming convention, although occasionally '''CYP450''' or '''CYP<sub>450</sub>''' is used synonymously. These names should never be used as according to the nomenclature convention (as they denote a P450 in family number 450). However, some gene or enzyme names for P450s are also referred to by historical names (e.g. P450<sub>BM3</sub> for CYP102A1) or functional names, denoting the catalytic activity and the name of the compound used as substrate. Examples include [[CYP5A1]], [[thromboxane]] A<sub>2</sub> synthase, abbreviated to [[Thromboxane-A synthase|TBXAS1]] ('''T'''hrom'''B'''o'''X'''ane '''A'''<sub>2</sub> '''S'''ynthase '''1'''), and [[CYP51A1]], lanosterol 14-α-demethylase, sometimes unofficially abbreviated to LDM according to its substrate ('''L'''anosterol) and activity ('''D'''e'''M'''ethylation).<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&id=3915660
|title=NCBI sequence viewer|access-date=2007-11-19}}</ref>
|title=NCBI sequence viewer|access-date=2007-11-19}}</ref>


The current nomenclature guidelines suggest that members of new CYP families share at least 40% [[amino acid|amino-acid]] identity, while members of subfamilies must share at least 55% amino-acid identity. Nomenclature committees assign and track both base gene names ([http://drnelson.uthsc.edu/CytochromeP450.html Cytochrome P450 Homepage]) and [[allele]] names ([https://www.pharmvar.org// CYP Allele Nomenclature Committee]).<ref>{{cite journal | vauthors = Nelson DR | title = The cytochrome p450 homepage | journal = Human Genomics | volume = 4 | issue = 1 | pages = 59–65 | date = October 2009 | pmid = 19951895 | pmc = 3500189 | doi = 10.1186/1479-7364-4-1-59 }}</ref><ref>{{cite journal | vauthors = Nelson DR | title = Progress in tracing the evolutionary paths of cytochrome P450 | journal = Biochimica et Biophysica Acta | volume = 1814 | issue = 1 | pages = 14–18 | date = January 2011 | pmid = 20736090 | doi = 10.1016/j.bbapap.2010.08.008 }}</ref>
The current nomenclature guidelines suggest that members of new CYP families share at least 40% [[amino acid|amino-acid]] identity, while members of subfamilies must share at least 55% amino-acid identity. Nomenclature committees assign and track both base gene names ([http://drnelson.uthsc.edu/CytochromeP450.html Cytochrome P450 Homepage] {{Webarchive|url=https://web.archive.org/web/20100627184446/http://drnelson.uthsc.edu/CytochromeP450.html |date=2010-06-27 }}) and [[allele]] names ([https://www.pharmvar.org// CYP Allele Nomenclature Committee]).<ref>{{cite journal | vauthors = Nelson DR | title = The cytochrome p450 homepage | journal = Human Genomics | volume = 4 | issue = 1 | pages = 59–65 | date = October 2009 | pmid = 19951895 | pmc = 3500189 | doi = 10.1186/1479-7364-4-1-59 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Nelson DR | title = Progress in tracing the evolutionary paths of cytochrome P450 | journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics | volume = 1814 | issue = 1 | pages = 14–18 | date = January 2011 | pmid = 20736090 | doi = 10.1016/j.bbapap.2010.08.008 }}</ref>


== Classification ==
== Classification ==
{{Main|P450-containing systems}}
{{Main|P450-containing systems}}
Based on the nature of the electron transfer proteins, CYPs can be classified into several groups:<ref name="1996-Hanukoglu">{{cite journal | vauthors = Hanukoglu I | title = Electron transfer proteins of cytochrome P450 systems | journal = Adv. Mol. Cell Biol. | year = 1996 | volume = 14 | pages= 29–55 | doi = 10.1016/S1569-2558(08)60339-2 | url=https://www.science.co.il/hi/pub/Electron-transfer-proteins-of-cytochrome-P450-systems.pdf| series = Advances in Molecular and Cell Biology | isbn = 9780762301133 }}</ref>
Based on the nature of the electron transfer proteins, P450s can be classified into several groups:<ref name="1996-Hanukoglu">{{cite journal | vauthors = Hanukoglu I | title = Electron transfer proteins of cytochrome P450 systems | journal = Adv. Mol. Cell Biol. | year = 1996 | volume = 14 | pages= 29–55 | doi = 10.1016/S1569-2558(08)60339-2 | url=https://www.science.co.il/hi/pub/Electron-transfer-proteins-of-cytochrome-P450-systems.pdf| series = Advances in Molecular and Cell Biology | isbn = 978-0-7623-0113-3 }}</ref>


;Microsomal P450 systems: in which electrons are transferred from [[nicotinamide adenine dinucleotide phosphate|NADPH]] via [[cytochrome P450 reductase]] (variously CPR, POR, or CYPOR). [[Cytochrome b5|Cytochrome b<sub>5</sub>]] (cyb<sub>5</sub>) can also contribute reducing power to this system after being reduced by [[cytochrome b5 reductase|cytochrome b<sub>5</sub> reductase]] (CYB<sub>5</sub>R).
;Microsomal P450 systems: in which electrons are transferred from [[nicotinamide adenine dinucleotide phosphate|NADPH]] via [[cytochrome P450 reductase]] (variously CPR, POR, or CYPOR). [[Cytochrome b5|Cytochrome b<sub>5</sub>]] (cyb<sub>5</sub>) can also contribute reducing power to this system after being reduced by [[cytochrome b5 reductase|cytochrome b<sub>5</sub> reductase]] (CYB<sub>5</sub>R).
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The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH), while the other oxygen atom is [[redox|reduced]] to water:
The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH), while the other oxygen atom is [[redox|reduced]] to water:
<center>
{{center|1=
RH + O<sub>2</sub> + NADPH + H<sup>+</sup> → ROH + H<sub>2</sub>O + NADP<sup>+</sup>
RH + O<sub>2</sub> + NADPH + H<sup>+</sup> → ROH + H<sub>2</sub>O + NADP<sup>+</sup>
</center> Many [[hydroxylation]] reactions (insertion of [[hydroxyl]] groups) use CYP enzymes.
}} Many [[hydroxylation]] reactions (insertion of [[hydroxyl]] groups) use CYP enzymes.


==Mechanism==
==Mechanism==
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=== Structure ===
=== Structure ===
The active site of cytochrome P450 contains a heme-iron center. The iron is tethered to the protein via a [[cysteine]] [[thiolate]] [[ligand]]. This cysteine and several flanking residues are highly conserved in known CYPs, and have the formal [[PROSITE]] signature consensus pattern [FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - <u>C</u> - [LIVMFAP] - [GAD].<ref>[http://www.expasy.org/cgi-bin/nicedoc.pl?PDOC00081][[PROSITE]] consensus pattern for P450</ref> Because of the vast variety of reactions catalyzed by CYPs, the activities and properties of the many CYPs differ in many aspects.<ref>{{cite journal | vauthors = Srinivasan B | title = Explicit Treatment of Non-Michaelis-Menten and Atypical Kinetics in Early Drug Discovery* | journal = ChemMedChem | volume = 16 | issue = 6 | pages = 899–918 | date = March 2021 | pmid = 33231926 | doi = 10.1002/cmdc.202000791 | s2cid = 227157473 }}</ref> In general, the P450 catalytic cycle proceeds as follows:
The active site of cytochrome P450 contains a heme-iron center. The iron is tethered to the protein via a [[cysteine]] [[thiolate]] [[ligand]]. This cysteine and several flanking residues are highly conserved in known P450s, and have the formal [[PROSITE]] signature consensus pattern [FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - <u>C</u> - [LIVMFAP] - [GAD].<ref>[http://www.expasy.org/cgi-bin/nicedoc.pl?PDOC00081] {{Webarchive|url=https://web.archive.org/web/20191018181235/https://web.expasy.org/cgi-bin/unavailable.cgi?type=redirect&query=nicedoc.pl|date=2019-10-18}} [[PROSITE]] consensus pattern for P450</ref> Because of the vast variety of reactions catalyzed by P450s, the activities and properties of the many P450s differ in many aspects. In general, the P450 catalytic cycle proceeds as follows:


===Catalytic cycle===
===Catalytic cycle===
# Substrate binds in proximity to the [[heme group]], on the side opposite to the axial thiolate. Substrate binding induces a change in the conformation of the active site, often displacing a water molecule from the distal axial coordination position of the heme iron,<ref name=P450Mechanism>{{cite journal | vauthors = Meunier B, de Visser SP, Shaik S | title = Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes | journal = Chemical Reviews | volume = 104 | issue = 9 | pages = 3947–3980 | date = September 2004 | pmid = 15352783 | doi = 10.1021/cr020443g | s2cid = 33927145 }}</ref> and changing the state of the heme iron from low-spin to high-spin.<ref name=HiResCam>{{cite journal | vauthors = Poulos TL, Finzel BC, Howard AJ | title = High-resolution crystal structure of cytochrome P450cam | journal = Journal of Molecular Biology | volume = 195 | issue = 3 | pages = 687–700 | date = June 1987 | pmid = 3656428 | doi = 10.1016/0022-2836(87)90190-2 }}</ref>
# Substrate binds in proximity to the [[heme group]], on the side opposite to the axial thiolate. Substrate binding induces a change in the conformation of the active site, often displacing a water molecule from the distal axial coordination position of the heme iron,<ref name=P450Mechanism>{{cite journal | vauthors = Meunier B, de Visser SP, Shaik S | title = Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes | journal = Chemical Reviews | volume = 104 | issue = 9 | pages = 3947–3980 | date = September 2004 | pmid = 15352783 | doi = 10.1021/cr020443g | s2cid = 33927145 }}</ref> and changing the state of the heme iron from low-spin to high-spin.<ref name=HiResCam>{{cite journal | vauthors = Poulos TL, Finzel BC, Howard AJ | title = High-resolution crystal structure of cytochrome P450cam | journal = Journal of Molecular Biology | volume = 195 | issue = 3 | pages = 687–700 | date = June 1987 | pmid = 3656428 | doi = 10.1016/0022-2836(87)90190-2 }}</ref>
# Substrate binding induces electron transfer from NAD(P)H via [[cytochrome P450 reductase]] or another associated [[reductase]].<ref name=P450pot>{{cite journal | vauthors = Sligar SG, Cinti DL, Gibson GG, Schenkman JB | title = Spin state control of the hepatic cytochrome P450 redox potential | journal = Biochemical and Biophysical Research Communications | volume = 90 | issue = 3 | pages = 925–932 | date = October 1979 | pmid = 228675 | doi = 10.1016/0006-291X(79)91916-8 }}</ref>
# Substrate binding induces electron transfer from NAD(P)H via [[cytochrome P450 reductase]] or another associated [[reductase]].<ref name=P450pot>{{cite journal | vauthors = Sligar SG, Cinti DL, Gibson GG, Schenkman JB | title = Spin state control of the hepatic cytochrome P450 redox potential | journal = Biochemical and Biophysical Research Communications | volume = 90 | issue = 3 | pages = 925–932 | date = October 1979 | pmid = 228675 | doi = 10.1016/0006-291X(79)91916-8 }}</ref>
# Molecular oxygen binds to the resulting ferrous heme center at the distal axial coordination position, initially giving a [[transition metal dioxygen complex|dioxygen adduct]] similar to oxy-myoglobin.
# Molecular oxygen binds to the resulting ferrous heme center at the distal axial coordination position, initially giving a [[transition metal dioxygen complex|dioxygen adduct]] similar to oxy-myoglobin.
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===Spectroscopy===
===Spectroscopy===
Binding of substrate is reflected in the spectral properties of the enzyme, with an increase in absorbance at 390&nbsp;nm and a decrease at 420&nbsp;nm. This can be measured by difference spectroscopies and is referred to as the "type&nbsp;I" difference spectrum (see inset graph in figure). Some substrates cause an opposite change in spectral properties, a "reverse type&nbsp;I" spectrum, by processes that are as yet unclear. Inhibitors and certain substrates that bind directly to the heme iron give rise to the type&nbsp;II difference spectrum, with a maximum at 430&nbsp;nm and a minimum at 390&nbsp;nm (see inset graph in figure). If no reducing equivalents are available, this complex may remain stable, allowing the degree of binding to be determined from absorbance measurements ''in vitro''<ref name=p450struc>{{cite book | vauthors = Ortiz de Montellano PR | title = Cytochrome P450: structure, mechanism, and biochemistry | edition = 3rd | publisher = Kluwer Academic/Plenum Publishers | location = New York | year = 2005 | isbn = 978-0-306-48324-0 }}</ref>
Binding of substrate is reflected in the spectral properties of the enzyme, with an increase in absorbance at 390&nbsp;nm and a decrease at 420&nbsp;nm. This can be measured by difference spectroscopies and is referred to as the "type&nbsp;I" difference spectrum (see inset graph in figure). Some substrates cause an opposite change in spectral properties, a "reverse type&nbsp;I" spectrum, by processes that are as yet unclear. Inhibitors and certain substrates that bind directly to the heme iron give rise to the type&nbsp;II difference spectrum, with a maximum at 430&nbsp;nm and a minimum at 390&nbsp;nm (see inset graph in figure). If no reducing equivalents are available, this complex may remain stable, allowing the degree of binding to be determined from absorbance measurements ''in vitro''<ref name=p450struc>{{cite book | vauthors = Ortiz de Montellano PR | title = Cytochrome P450: structure, mechanism, and biochemistry | edition = 3rd | publisher = Kluwer Academic/Plenum Publishers | location = New York | year = 2005 | isbn = 978-0-306-48324-0 }}</ref>
C: If carbon monoxide (CO) binds to reduced P450, the catalytic cycle is interrupted. This reaction yields the classic CO difference spectrum with a maximum at 450&nbsp;nm. However, the interruptive and inhibitory effects of CO varies upon different CYPs such that the CYP3A family is relatively less affected.<ref>{{cite journal | vauthors = Hopper CP, Zambrana PN, Goebel U, Wollborn J | title = A brief history of carbon monoxide and its therapeutic origins | journal = Nitric Oxide | volume = 111-112 | pages = 45–63 | date = June 2021 | pmid = 33838343 | doi = 10.1016/j.niox.2021.04.001 }}</ref>
C: If carbon monoxide (CO) binds to reduced P450, the catalytic cycle is interrupted. This reaction yields the classic CO difference spectrum with a maximum at 450&nbsp;nm. However, the interruptive and inhibitory effects of CO varies upon different CYPs such that the CYP3A family is relatively less affected.<ref>{{cite journal | vauthors = Hopper CP, Zambrana PN, Goebel U, Wollborn J | title = A brief history of carbon monoxide and its therapeutic origins | journal = Nitric Oxide | volume = 111-112 | pages = 45–63 | date = June 2021 | pmid = 33838343 | doi = 10.1016/j.niox.2021.04.001 | s2cid = 233205099 }}</ref>


==P450s in humans==
==P450s in humans==
Human CYPs are primarily membrane-associated proteins<ref name="pmid21744854">{{cite journal | vauthors = Berka K, Hendrychová T, Anzenbacher P, Otyepka M | title = Membrane position of ibuprofen agrees with suggested access path entrance to cytochrome P450 2C9 active site | journal = The Journal of Physical Chemistry. A | volume = 115 | issue = 41 | pages = 11248–11255 | date = October 2011 | pmid = 21744854 | pmc = 3257864 | doi = 10.1021/jp204488j | bibcode = 2011JPCA..11511248B }}</ref> located either in the inner membrane of [[mitochondria]] or in the [[endoplasmic reticulum]] of cells. CYPs metabolize thousands of [[endogenous]] and [[exogenous]] chemicals. Some CYPs metabolize only one (or a very few) substrates, such as ''CYP19'' ([[aromatase]]), while others may metabolize multiple [[Substrate (biochemistry)|substrates]]. Both of these characteristics account for their central importance in [[medicine]]. Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in [[hormone]] synthesis and breakdown (including [[estrogen]] and [[testosterone]] synthesis and metabolism), [[cholesterol]] synthesis, and [[vitamin D]] metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including [[drugs]] and products of endogenous metabolism such as [[bilirubin]], principally in the [[liver]].
Human P450s are primarily membrane-associated proteins<ref name="pmid21744854">{{cite journal | vauthors = Berka K, Hendrychová T, Anzenbacher P, Otyepka M | title = Membrane position of ibuprofen agrees with suggested access path entrance to cytochrome P450 2C9 active site | journal = The Journal of Physical Chemistry A | volume = 115 | issue = 41 | pages = 11248–11255 | date = October 2011 | pmid = 21744854 | pmc = 3257864 | doi = 10.1021/jp204488j | bibcode = 2011JPCA..11511248B }}</ref> located either in the inner membrane of [[mitochondria]] or in the [[endoplasmic reticulum]] of cells. P450s metabolize thousands of [[endogenous]] and [[exogenous]] chemicals. Some P450s metabolize only one (or a very few) substrates, such as ''CYP19'' ([[aromatase]]), while others may metabolize multiple [[Substrate (biochemistry)|substrates]]. Both of these characteristics account for their central importance in [[medicine]]. Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in [[hormone]] synthesis and breakdown (including [[estrogen]] and [[testosterone]] synthesis and metabolism), [[cholesterol]] synthesis, and [[vitamin D]] metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including [[drugs]] and products of endogenous metabolism such as [[bilirubin]], principally in the [[liver]].


The [[Human Genome Project]] has identified 57 human genes coding for the various cytochrome P450 enzymes.<ref name="P450table">{{Cite web|title=P450 Table
The [[Human Genome Project]] has identified 57 human genes coding for the various cytochrome P450 enzymes.<ref name="P450table">{{Cite web|title=P450 Table
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===Drug metabolism===
===Drug metabolism===
[[File:PropDrugsMetabCYP.png|thumb|400px|Proportion of antifungal drugs metabolized by different families of CYPs.<ref>[http://www.doctorfungus.org/thedrugs/antif_interaction.php doctorfungus > Antifungal Drug Interactions] {{webarchive|url=https://archive.today/20120801072859/http://www.doctorfungus.org/thedrugs/antif_interaction.php |date=2012-08-01 }} Content Director: Russell E. Lewis, Pharm.D. Retrieved on Jan 23, 2010</ref>]]
[[File:PropDrugsMetabCYP.png|thumb|400px|Proportion of antifungal drugs metabolized by different families of P450s.<ref>[http://www.doctorfungus.org/thedrugs/antif_interaction.php doctorfungus > Antifungal Drug Interactions] {{webarchive|url=https://archive.today/20120801072859/http://www.doctorfungus.org/thedrugs/antif_interaction.php |date=2012-08-01 }} Content Director: Russell E. Lewis, Pharm.D. Retrieved on Jan 23, 2010</ref>]]


{{Further|Drug metabolism}}
{{Further|Drug metabolism}}
CYPs are the major enzymes involved in [[drug metabolism]], accounting for about 75% of the total metabolism.<ref name="pmid18052394">{{cite journal | vauthors = Guengerich FP | title = Cytochrome p450 and chemical toxicology | journal = Chemical Research in Toxicology | volume = 21 | issue = 1 | pages = 70–83 | date = January 2008 | pmid = 18052394 | doi = 10.1021/tx700079z | s2cid = 17548932 }} (Metabolism in this context is the chemical modification or degradation of drugs.)</ref> Most drugs undergo deactivation by CYPs, either directly or by facilitated [[excretion]] from the body. Also, many substances are [[bioactivation|bioactivated]] by CYPs to form their active compounds like the [[antiplatelet drug]] [[clopidogrel]] and the opiate [[codeine]].
P450s are the major enzymes involved in [[drug metabolism]], accounting for about 75% of the total metabolism.<ref name="pmid18052394">{{cite journal | vauthors = Guengerich FP | title = Cytochrome p450 and chemical toxicology | journal = Chemical Research in Toxicology | volume = 21 | issue = 1 | pages = 70–83 | date = January 2008 | pmid = 18052394 | doi = 10.1021/tx700079z | s2cid = 17548932 }} (Metabolism in this context is the chemical modification or degradation of drugs.)</ref> Most drugs undergo deactivation by P450s, either directly or by facilitated [[excretion]] from the body. However, many substances are [[bioactivation|bioactivated]] by P450s to form their active compounds like the [[antiplatelet drug]] [[clopidogrel]] and the opiate [[codeine]].

The CYP450 enzyme superfamily comprises 57 active subsets, with seven playing a crucial role in the metabolism of most pharmaceuticals.<ref>{{Cite journal |last=Bains |first=Ripudaman K. |date=2013 |title=African variation at Cytochrome P450 genes |journal=Evolution, Medicine, and Public Health |language=en |volume=2013 |issue=1 |pages=118–134 |doi=10.1093/emph/eot010 |issn=2050-6201 |pmc=3868406 |pmid=24481193}}</ref> The fluctuation in the amount of CYP450 enzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) in phase 1 (detoxification) can have varying effects on individuals, as genetic expression varies from person to person. This variation is due to the enzyme’s genetic polymorphism, which leads to variability in its function and expression. To optimize drug metabolism in individuals, genetic testing should be conducted to determine functional foods and specific phytonutrients that cater to the individual’s CYP450 polymorphism. Understanding these genetic variations can help personalize drug therapies for improved effectiveness and reduced adverse reactions.<ref>{{Cite journal |last1=Hodges |first1=Romilly E. |last2=Minich |first2=Deanna M. |date=2015 |title=Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application |journal=Journal of Nutrition and Metabolism |language=en |volume=2015 |pages=1–23 |doi=10.1155/2015/760689 |doi-access=free |pmid=26167297 |pmc=4488002 |issn=2090-0724}}</ref>


====Drug interaction====
====Drug interaction====
Many drugs may increase or decrease the activity of various CYP [[isozyme]]s either by inducing the biosynthesis of an isozyme ([[Regulation of gene expression|enzyme induction]]) or by directly inhibiting the activity of the CYP ([[enzyme inhibition]]). A classical example includes [[Anticonvulsant|anti-epileptic drugs]], such as [[Phenytoin]], which induces [[CYP1A2]], [[CYP2C9]], [[CYP2C19]], and [[CYP3A4]].
Many drugs may increase or decrease the activity of various P450 [[isozyme]]s either by inducing the biosynthesis of an isozyme ([[Regulation of gene expression|enzyme induction]]) or by directly inhibiting the activity of the P450 ([[enzyme inhibition]]). A classical example includes [[Anticonvulsant|anti-epileptic drugs]], such as [[phenytoin]], which induces [[CYP1A2]], [[CYP2C9]], [[CYP2C19]], and [[CYP3A4]].


Effects on CYP isozyme activity are a major source of adverse [[drug interaction]]s, since changes in CYP enzyme activity may affect the [[drug metabolism|metabolism]] and [[medical clearance|clearance]] of various drugs. For example, if one drug inhibits the CYP-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels. Hence, these drug interactions may necessitate dosage adjustments or choosing drugs that do not interact with the CYP system. Such drug interactions are especially important to consider when using drugs of vital importance to the patient, drugs with significant [[adverse effect|side-effects]], or drugs with a narrow [[therapeutic index]], but any drug may be subject to an altered plasma concentration due to altered drug metabolism.
Effects on P450 isozyme activity are a major source of adverse [[drug interaction]]s, since changes in P450 enzyme activity may affect the [[drug metabolism|metabolism]] and [[medical clearance|clearance]] of various drugs. For example, if one drug inhibits the P450-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels. Hence, these drug interactions may necessitate dosage adjustments or choosing drugs that do not interact with the P450 system. Such drug interactions are especially important to consider when using drugs of vital importance to the patient, drugs with significant [[adverse effect|side-effects]], or drugs with a narrow [[therapeutic index]], but any drug may be subject to an altered plasma concentration due to altered drug metabolism.


Many substrates for CYP3A4 are drugs with a narrow [[therapeutic index]], such as [[amiodarone]]<ref>{{cite journal | vauthors = Zahno A, Brecht K, Morand R, Maseneni S, Török M, Lindinger PW, Krähenbühl S | title = The role of CYP3A4 in amiodarone-associated toxicity on HepG2 cells | journal = Biochemical Pharmacology | volume = 81 | issue = 3 | pages = 432–441 | date = February 2011 | pmid = 21070748 | doi = 10.1016/j.bcp.2010.11.002 }}</ref> or [[carbamazepine]].<ref>{{cite news |title=Carbamazepine: Watch for Many Potential Drug Interactions |url=https://www.pharmacytimes.com/publications/issue/2008/2008-02/2008-02-8414 |work=Pharmacy Times}}</ref> Because these drugs are metabolized by CYP3A4, the [[mean plasma levels]] of these drugs may increase because of enzyme inhibition or decrease because of enzyme induction.
Many substrates for CYP3A4 are drugs with a narrow [[therapeutic index]], such as [[amiodarone]]<ref>{{cite journal | vauthors = Zahno A, Brecht K, Morand R, Maseneni S, Török M, Lindinger PW, Krähenbühl S | title = The role of CYP3A4 in amiodarone-associated toxicity on HepG2 cells | journal = Biochemical Pharmacology | volume = 81 | issue = 3 | pages = 432–441 | date = February 2011 | pmid = 21070748 | doi = 10.1016/j.bcp.2010.11.002 }}</ref> or [[carbamazepine]].<ref>{{cite news |title=Carbamazepine: Watch for Many Potential Drug Interactions |url=https://www.pharmacytimes.com/publications/issue/2008/2008-02/2008-02-8414 |work=Pharmacy Times |access-date=2019-11-07 |archive-date=2020-10-14 |archive-url=https://web.archive.org/web/20201014100433/https://www.pharmacytimes.com/publications/issue/2008/2008-02/2008-02-8414 |url-status=dead }}</ref> Because these drugs are metabolized by CYP3A4, the [[mean plasma levels]] of these drugs may increase because of enzyme inhibition or decrease because of enzyme induction.


====Interaction of other substances====
====Interaction of other substances====
Naturally occurring compounds may also induce or inhibit CYP activity. For example, [[Bioactive compound|bioactive]] compounds found in [[grapefruit juice]] and some other fruit juices, including [[bergamottin]], [[dihydroxybergamottin]], and [[paradicin-A]], have been found to inhibit CYP3A4-mediated metabolism of [[Grapefruit–drug interactions|certain medications]], leading to increased [[bioavailability]] and, thus, the strong possibility of [[overdosing]].<ref name="pmid15449971">{{cite journal | vauthors = Bailey DG, Dresser GK | title = Interactions between grapefruit juice and cardiovascular drugs | journal = American Journal of Cardiovascular Drugs | volume = 4 | issue = 5 | pages = 281–297 | year = 2004 | pmid = 15449971 | doi = 10.2165/00129784-200404050-00002 | s2cid = 11525439 }}</ref> Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.<ref name="urlGrapefruit juice: Can it cause drug interactions? - MayoClinic.com">{{cite web | url = http://www.mayoclinic.com/health/food-and-nutrition/AN00413 | title = Grapefruit juice: Can it cause drug interactions? | author = Zeratsky K | date = 2008-11-06 | work = Ask a food & nutrition specialist | publisher = MayoClinic.com | access-date = 2009-02-09}}</ref>
Naturally occurring compounds may also induce or inhibit P450 activity. For example, [[Bioactive compound|bioactive]] compounds found in [[grapefruit juice]] and some other fruit juices, including [[bergamottin]], [[dihydroxybergamottin]], and [[paradicin-A]], have been found to inhibit CYP3A4-mediated metabolism of [[Grapefruit–drug interactions|certain medications]], leading to increased [[bioavailability]] and, thus, the strong possibility of [[overdosing]].<ref name="pmid15449971">{{cite journal | vauthors = Bailey DG, Dresser GK | title = Interactions between grapefruit juice and cardiovascular drugs | journal = American Journal of Cardiovascular Drugs | volume = 4 | issue = 5 | pages = 281–297 | year = 2004 | pmid = 15449971 | doi = 10.2165/00129784-200404050-00002 | s2cid = 11525439 }}</ref> Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.<ref name="urlGrapefruit juice: Can it cause drug interactions? - MayoClinic.com">{{cite web | url = http://www.mayoclinic.com/health/food-and-nutrition/AN00413 | title = Grapefruit juice: Can it cause drug interactions? | author = Zeratsky K | date = 2008-11-06 | work = Ask a food & nutrition specialist | publisher = MayoClinic.com | access-date = 2009-02-09}}</ref>


Other examples:
Other examples:
*[[Saint-John's wort]], a common [[herbal remedy]] [[Regulation of gene expression|induces]] [[CYP3A4]], but also inhibits [[CYP1A1]], [[CYP1B1]].<ref name="pmid16271822">{{cite journal | vauthors = Chaudhary A, Willett KL | title = Inhibition of human cytochrome CYP 1 enzymes by flavonoids of St. John's wort | journal = Toxicology | volume = 217 | issue = 2-3 | pages = 194–205 | date = January 2006 | pmid = 16271822 | doi = 10.1016/j.tox.2005.09.010 }}</ref><ref name="pmid15070158">{{cite journal | vauthors = Strandell J, Neil A, Carlin G | title = An approach to the in vitro evaluation of potential for cytochrome P450 enzyme inhibition from herbals and other natural remedies | journal = Phytomedicine | volume = 11 | issue = 2-3 | pages = 98–104 | date = February 2004 | pmid = 15070158 | doi = 10.1078/0944-7113-00379 }}</ref>
* [[Saint-John's wort]], a common [[herbal remedy]] [[Regulation of gene expression|induces]] [[CYP3A4]], but also inhibits [[CYP1A1]], [[CYP1B1]].<ref name="pmid16271822">{{cite journal | vauthors = Chaudhary A, Willett KL | title = Inhibition of human cytochrome CYP 1 enzymes by flavonoids of St. John's wort | journal = Toxicology | volume = 217 | issue = 2–3 | pages = 194–205 | date = January 2006 | pmid = 16271822 | doi = 10.1016/j.tox.2005.09.010 }}</ref><ref name="pmid15070158">{{cite journal | vauthors = Strandell J, Neil A, Carlin G | title = An approach to the in vitro evaluation of potential for cytochrome P450 enzyme inhibition from herbals and other natural remedies | journal = Phytomedicine | volume = 11 | issue = 2–3 | pages = 98–104 | date = February 2004 | pmid = 15070158 | doi = 10.1078/0944-7113-00379 }}</ref>
*[[Tobacco smoking]] induces [[CYP1A2]] (example CYP1A2 substrates are [[clozapine]], [[olanzapine]], and [[fluvoxamine]])<ref name="pmid17823102">{{cite journal | vauthors = Kroon LA | title = Drug interactions with smoking | journal = American Journal of Health-System Pharmacy | volume = 64 | issue = 18 | pages = 1917–1921 | date = September 2007 | pmid = 17823102 | doi = 10.2146/ajhp060414 | s2cid = 5397510 }}</ref>
* [[Tobacco smoking]] induces [[CYP1A2]] (example CYP1A2 substrates are [[clozapine]], [[olanzapine]], and [[fluvoxamine]])<ref name="pmid17823102">{{cite journal | vauthors = Kroon LA | title = Drug interactions with smoking | journal = American Journal of Health-System Pharmacy | volume = 64 | issue = 18 | pages = 1917–1921 | date = September 2007 | pmid = 17823102 | doi = 10.2146/ajhp060414 | s2cid = 5397510 }}</ref>
*At relatively high concentrations, [[carambola|starfruit]] juice has also been shown to inhibit [[CYP2A6]] and other CYPs.<ref name="pmid18261370">{{cite journal | vauthors = Zhang JW, Liu Y, Cheng J, Li W, Ma H, Liu HT, Sun J, Wang LM, He YQ, Wang Y, Wang ZT, Yang L | display-authors = 6 | title = Inhibition of human liver cytochrome P450 by star fruit juice | journal = Journal of Pharmacy & Pharmaceutical Sciences | volume = 10 | issue = 4 | pages = 496–503 | year = 2007 | pmid = 18261370 | doi = 10.18433/j30593 | doi-access = free }}</ref> [[Watercress]] is also a known inhibitor of the cytochrome P450 [[CYP2E1]], which may result in altered drug metabolism for individuals on certain medications (e.g., [[chlorzoxazone]]).<ref>{{cite journal | vauthors = Leclercq I, Desager JP, Horsmans Y | title = Inhibition of chlorzoxazone metabolism, a clinical probe for CYP2E1, by a single ingestion of watercress | journal = Clinical Pharmacology and Therapeutics | volume = 64 | issue = 2 | pages = 144–149 | date = August 1998 | pmid = 9728894 | doi = 10.1016/S0009-9236(98)90147-3 | s2cid = 43863786 }}</ref>
* At relatively high concentrations, [[carambola|starfruit]] juice has also been shown to inhibit [[CYP2A6]] and other P450s.<ref name="pmid18261370">{{cite journal | vauthors = Zhang JW, Liu Y, Cheng J, Li W, Ma H, Liu HT, Sun J, Wang LM, He YQ, Wang Y, Wang ZT, Yang L | display-authors = 6 | title = Inhibition of human liver cytochrome P450 by star fruit juice | journal = Journal of Pharmacy & Pharmaceutical Sciences | volume = 10 | issue = 4 | pages = 496–503 | year = 2007 | pmid = 18261370 | doi = 10.18433/j30593 | doi-access = free }}</ref> [[Watercress]] is also a known inhibitor of the cytochrome P450 [[CYP2E1]], which may result in altered drug metabolism for individuals on certain medications (e.g., [[chlorzoxazone]]).<ref>{{cite journal | vauthors = Leclercq I, Desager JP, Horsmans Y | title = Inhibition of chlorzoxazone metabolism, a clinical probe for CYP2E1, by a single ingestion of watercress | journal = Clinical Pharmacology and Therapeutics | volume = 64 | issue = 2 | pages = 144–149 | date = August 1998 | pmid = 9728894 | doi = 10.1016/S0009-9236(98)90147-3 | s2cid = 43863786 }}</ref>
* [[Tributyltin]] has been found to inhibit the function of cytochrome P450, leading to masculinization of mollusks.<ref name=WWF>{{cite web| vauthors = Walmsley S |title=Tributyltin pollution on a global scale. An overview of relevant and recent research: impacts and issues.|url=http://assets.wwf.no/downloads/tbt_global_review_wwf_uk_oct_2006.pdf|publisher=WWF UK}}</ref>
* [[Tributyltin]] has been found to inhibit the function of cytochrome P450, leading to masculinization of mollusks.<ref name=WWF>{{cite web|vauthors=Walmsley S|title=Tributyltin pollution on a global scale. An overview of relevant and recent research: impacts and issues.|url=http://assets.wwf.no/downloads/tbt_global_review_wwf_uk_oct_2006.pdf|publisher=WWF UK|access-date=2014-05-01|archive-date=2014-04-07|archive-url=https://web.archive.org/web/20140407101845/http://assets.wwf.no/downloads/tbt_global_review_wwf_uk_oct_2006.pdf|url-status=dead}}</ref>
* [[Goldenseal]], with its two notable alkaloids [[berberine]] and [[hydrastine]], has been shown to alter P450-marker enzymatic activities (involving CYP2C9, CYP2D6, and CYP3A4).<ref>{{cite journal | vauthors = Chatterjee P, Franklin MR | title = Human cytochrome p450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylenedioxyphenyl components | journal = Drug Metabolism and Disposition | volume = 31 | issue = 11 | pages = 1391–1397 | date = November 2003 | pmid = 14570772 | doi = 10.1124/dmd.31.11.1391 | s2cid = 2967171 }}</ref>
* [[Goldenseal]], with its two notable alkaloids [[berberine]] and [[hydrastine]], has been shown to alter P450-marker enzymatic activities (involving CYP2C9, CYP2D6, and CYP3A4).<ref>{{cite journal | vauthors = Chatterjee P, Franklin MR | title = Human cytochrome p450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylenedioxyphenyl components | journal = Drug Metabolism and Disposition | volume = 31 | issue = 11 | pages = 1391–1397 | date = November 2003 | pmid = 14570772 | doi = 10.1124/dmd.31.11.1391 | s2cid = 2967171 }}</ref>


===Other specific CYP functions===
===Other specific P450 functions===


====Steroid hormones====
====Steroid hormones====
[[File:Steroidogenesis.svg|thumb|400px|[[Steroidogenesis]], showing many of the enzyme activities that are performed by cytochrome P450 enzymes.<ref name="HäggströmRichfield2014">{{cite journal | vauthors = Häggström M, Richfield D |year=2014|title=Diagram of the pathways of human steroidogenesis|journal=WikiJournal of Medicine|volume=1|issue=1|doi=10.15347/wjm/2014.005|issn=2002-4436 |doi-access=free}}</ref> HSD: Hydroxysteroid dehydrogenase.]]
[[File:Steroidogenesis.svg|thumb|400px|[[Steroidogenesis]], showing many of the enzyme activities that are performed by cytochrome P450 enzymes.<ref name="HäggströmRichfield2014">{{cite journal | vauthors = Häggström M, Richfield D |year=2014|title=Diagram of the pathways of human steroidogenesis|journal=WikiJournal of Medicine|volume=1|issue=1|doi=10.15347/wjm/2014.005|issn=2002-4436 |doi-access=free}}</ref> HSD: Hydroxysteroid dehydrogenase.]]
A subset of cytochrome P450 enzymes play important roles in the synthesis of [[steroid hormone]]s ([[steroidogenesis]]) by the [[adrenal gland|adrenal]]s, [[gonad]]s, and peripheral tissue:
A subset of cytochrome P450 enzymes play important roles in the synthesis of [[steroid hormone]]s ([[steroidogenesis]]) by the [[adrenal gland|adrenal]]s, [[gonad]]s, and peripheral tissue:
*[[CYP11A1]] (also known as P450scc or P450c11a1) in adrenal [[mitochondrion|mitochondria]] affects "the activity formerly known as 20,22-desmolase" (steroid 20α-hydroxylase, steroid 22-hydroxylase, cholesterol [[Side chain|side-chain]] scission).
* [[CYP11A1]] (also known as P450scc or P450c11a1) in adrenal [[mitochondrion|mitochondria]] affects "the activity formerly known as 20,22-desmolase" (steroid 20α-hydroxylase, steroid 22-hydroxylase, cholesterol [[Side chain|side-chain]] scission).
*[[CYP11B1]] (encoding the protein P450c11β) found in the [[inner mitochondrial membrane]] of [[adrenal cortex]] has steroid 11β-hydroxylase, steroid [[18-hydroxylase]], and steroid 18-methyloxidase activities.
* [[CYP11B1]] (encoding the protein P450c11β) found in the [[inner mitochondrial membrane]] of [[adrenal cortex]] has steroid 11β-hydroxylase, steroid [[18-hydroxylase]], and steroid 18-methyloxidase activities.
*[[CYP11B2]] (encoding the protein P450c11AS), found only in the mitochondria of the adrenal [[zona glomerulosa]], has steroid 11β-hydroxylase, steroid 18-hydroxylase, and steroid 18-methyloxidase activities.
* [[CYP11B2]] (encoding the protein P450c11AS), found only in the mitochondria of the adrenal [[zona glomerulosa]], has steroid 11β-hydroxylase, steroid 18-hydroxylase, and steroid 18-methyloxidase activities.
*[[CYP17A1]], in endoplasmic reticulum of adrenal cortex has steroid 17α-hydroxylase and 17,20-lyase activities.
* [[CYP17A1]], in endoplasmic reticulum of adrenal cortex has steroid 17α-hydroxylase and 17,20-lyase activities.
*[[CYP21A2]] (P450c21) in adrenal cortex conducts [[21-hydroxylase]] activity.
* [[CYP21A2]] (P450c21) in adrenal cortex conducts [[21-hydroxylase]] activity.
*[[CYP19A]] (P450arom, [[aromatase]]) in [[endoplasmic reticulum]] of [[gonads]], [[brain]], [[adipose tissue]], and elsewhere catalyzes [[aromatization]] of [[androgens]] to [[estrogens]].
* [[CYP19A]] (P450arom, [[aromatase]]) in [[endoplasmic reticulum]] of [[gonads]], [[brain]], [[adipose tissue]], and elsewhere catalyzes [[aromatization]] of [[androgens]] to [[estrogens]].


====Polyunsaturated fatty acids and eicosanoids====
====Polyunsaturated fatty acids and eicosanoids====
Certain cytochrome P450 enzymes are critical in metabolizing [[polyunsaturated fatty acid]]s (PUFAs) to biologically active, intercellular [[cell signaling]] molecules ([[eicosanoid]]s) and/or metabolize biologically active metabolites of the PUFA to less active or inactive products. These CYPs possess [[cytochrome P450 omega hydroxylase]] and/or [[epoxygenase]] enzyme activity.
Certain cytochrome P450 enzymes are critical in metabolizing [[polyunsaturated fatty acid]]s (PUFAs) to biologically active, intercellular [[cell signaling]] molecules ([[eicosanoid]]s) and/or metabolize biologically active metabolites of the PUFA to less active or inactive products. These CYPs possess [[cytochrome P450 omega hydroxylase]] and/or [[epoxygenase]] enzyme activity.
*[[CYP1A1]], [[CYP1A2]], and [[CYP2E1]] metabolize endogenous PUFAs to signaling molecules: they metabolize [[arachidonic acid]] (i.e. AA) to 19-hydroxyeicosatetraenoic acid (i.e. 19-HETE; see [[20-Hydroxyeicosatetraenoic acid|20-hydroxyeicosatetraenoic acid]]); [[eicosapentaenoic acid]] (i.e. EPA) to [[epoxyeicosatetraenoic acid]]s (i.e. EEQs); and [[docosahexaenoic acid]] (i.e. DHA) to [[epoxydocosapentaenoic acid]]s (i.e. EDPs).
* [[CYP1A1]], [[CYP1A2]], and [[CYP2E1]] metabolize endogenous PUFAs to signaling molecules: they metabolize [[arachidonic acid]] (i.e. AA) to 19-hydroxyeicosatetraenoic acid (i.e. 19-HETE; see [[20-Hydroxyeicosatetraenoic acid|20-hydroxyeicosatetraenoic acid]]); [[eicosapentaenoic acid]] (i.e. EPA) to [[epoxyeicosatetraenoic acid]]s (i.e. EEQs); and [[docosahexaenoic acid]] (i.e. DHA) to [[epoxydocosapentaenoic acid]]s (i.e. EDPs).
*[[CYP2C8]], [[CYP2C9]], [[CYP2C18]], [[CYP2C19]], and [[CYP2J2]] metabolize endogenous PUFAs to signaling molecules: they metabolize AA to [[epoxyeicosatetraenoic acid]]s (i.e. EETs); EPA to EEQs; and DHA to EDPs.
* [[CYP2C8]], [[CYP2C9]], [[CYP2C18]], [[CYP2C19]], and [[CYP2J2]] metabolize endogenous PUFAs to signaling molecules: they metabolize AA to [[epoxyeicosatetraenoic acid]]s (i.e. EETs); EPA to EEQs; and DHA to EDPs.
*[[CYP2S1]] metabolizes PUFA to signaling molecules: it metabolizes AA to EETs and EPA to EEQs.
* [[CYP2S1]] metabolizes PUFA to signaling molecules: it metabolizes AA to EETs and EPA to EEQs.
*[[CYP3A4]] metabolizes AA to EET signaling molecules.
* [[CYP3A4]] metabolizes AA to EET signaling molecules.
*[[CYP4A11]] metabolizes endogenous PUFAs to signaling molecules: it metabolizes AA to 20-HETE and EETs; it also hydroxylates DHA to 22-hydroxy-DHA (i.e. 12-HDHA).
* [[CYP4A11]] metabolizes endogenous PUFAs to signaling molecules: it metabolizes AA to 20-HETE and EETs; it also hydroxylates DHA to 22-hydroxy-DHA (i.e. 12-HDHA).
*[[CYP4F2]], CYP4F3A, and CYP4F3B (see [[CYP4F3]] for latter two CYPs) metabolize PUFAs to signaling molecules: they metabolizes AA to 20-HETE. They also metabolize EPA to 19-hydroxyeicosapentaenoic acid (19-HEPE) and 20-hydroxyeicosapentaenoic acid (20-HEPE) as well as metabolize DHA to 22-HDA. They also inactivate or reduce the activity of signaling molecules: they metabolize [[leukotriene B4]] (LTB4) to 20-hydroxy-LTB4, [[5-hydroxyeicosatetraenoic acid]] (5-HETE) to 5,20-diHETE, [[5-oxo-eicosatetraenoic acid]] (5-oxo-ETE) to 5-oxo,20-hydroxy-ETE, [[12-hydroxyeicosatetraenoic acid]] (12-HETE) to 12,20-diHETE, EETs to 20-hydroxy-EETs, and [[lipoxin]]s to 20-hydroxy products.
* [[CYP4F2]], CYP4F3A, and CYP4F3B (see [[CYP4F3]] for latter two CYPs) metabolize PUFAs to signaling molecules: they metabolizes AA to 20-HETE. They also metabolize EPA to 19-hydroxyeicosapentaenoic acid (19-HEPE) and 20-hydroxyeicosapentaenoic acid (20-HEPE) as well as metabolize DHA to 22-HDA. They also inactivate or reduce the activity of signaling molecules: they metabolize [[leukotriene B4]] (LTB4) to 20-hydroxy-LTB4, [[5-hydroxyeicosatetraenoic acid]] (5-HETE) to 5,20-diHETE, [[5-oxo-eicosatetraenoic acid]] (5-oxo-ETE) to 5-oxo,20-hydroxy-ETE, [[12-hydroxyeicosatetraenoic acid]] (12-HETE) to 12,20-diHETE, EETs to 20-hydroxy-EETs, and [[lipoxin]]s to 20-hydroxy products.
*[[CYP4F8]] and [[CYP4F12]] metabolize PUFAs to signaling molecules: they metabolizes EPA to EEQs and DHA to EDPs. They also metabolize AA to 18-hydroxyeicosatetraenoic acid (18-HETE) and 19-HETE.
* [[CYP4F8]] and [[CYP4F12]] metabolize PUFAs to signaling molecules: they metabolizes EPA to EEQs and DHA to EDPs. They also metabolize AA to 18-hydroxyeicosatetraenoic acid (18-HETE) and 19-HETE.
*[[CYP4F11]] inactivates or reduces the activity of signaling molecules: it metabolizes LTB4 to 20-hydroxy-LTB4, (5-HETE) to 5,20-diHETE, (5-oxo-ETE) to 5-oxo,20-hydroxy-ETE, (12-HETE) to 12,20-diHETE, EETs to 20-hydroxy-EETs, and [[lipoxin]]s to 20-hydroxy products.
* [[CYP4F11]] inactivates or reduces the activity of signaling molecules: it metabolizes LTB4 to 20-hydroxy-LTB4, (5-HETE) to 5,20-diHETE, (5-oxo-ETE) to 5-oxo,20-hydroxy-ETE, (12-HETE) to 12,20-diHETE, (15-HETE) to 15,20-diHETE, EETs to 20-hydroxy-EETs, and [[lipoxin]]s to 20-hydroxy products.
*[[CYP4F22]] ω-hydroxylates extremely long "[[very long chain fatty acids]]", i.e. fatty acids that are 28 or more carbons long. The ω-hydroxylation of these special fatty acids is critical to creating and maintaining the skin's water barrier function; autosomal recessive inactivating mutations of CYP4F22 are associated with the [[Lamellar ichthyosis]] subtype of [[Congenital ichthyosiform erythrodema]] in humans.<ref>{{cite journal | vauthors = Sugiura K, Akiyama M | title = Update on autosomal recessive congenital ichthyosis: mRNA analysis using hair samples is a powerful tool for genetic diagnosis | journal = Journal of Dermatological Science | volume = 79 | issue = 1 | pages = 4–9 | date = July 2015 | pmid = 25982146 | doi = 10.1016/j.jdermsci.2015.04.009 }}</ref>
* [[CYP4F22]] ω-hydroxylates extremely long "[[very long chain fatty acids]]", i.e. fatty acids that are 28 or more carbons long. The ω-hydroxylation of these special fatty acids is critical to creating and maintaining the skin's water barrier function; autosomal recessive inactivating mutations of CYP4F22 are associated with the [[Lamellar ichthyosis]] subtype of [[Congenital ichthyosiform erythrodema]] in humans.<ref>{{cite journal | vauthors = Sugiura K, Akiyama M | title = Update on autosomal recessive congenital ichthyosis: mRNA analysis using hair samples is a powerful tool for genetic diagnosis | journal = Journal of Dermatological Science | volume = 79 | issue = 1 | pages = 4–9 | date = July 2015 | pmid = 25982146 | doi = 10.1016/j.jdermsci.2015.04.009 }}</ref>


===CYP families in humans===
===CYP families in humans===
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| '''CYP4''' || [[arachidonic acid]] or fatty acid metabolism || 6 subfamilies, 12 genes, 10 [[pseudogene]]s || [[CYP4A11]], [[CYP4A22]], [[CYP4B1]], [[CYP4F2]], [[CYP4F3]], [[CYP4F8]], [[CYP4F11]], [[CYP4F12]], [[CYP4F22]], [[CYP4V2]], [[CYP4X1]], [[CYP4Z1]] || Too many to list
| '''CYP4''' || [[arachidonic acid]] or fatty acid metabolism || 6 subfamilies, 12 genes, 10 [[pseudogene]]s || [[CYP4A11]], [[CYP4A22]], [[CYP4B1]], [[CYP4F2]], [[CYP4F3]], [[CYP4F8]], [[CYP4F11]], [[CYP4F12]], [[CYP4F22]], [[CYP4V2]], [[CYP4X1]], [[CYP4Z1]] || Too many to list
|-
|-
| '''CYP5''' || [[thromboxane]] A<sub>2</sub> [[thromboxane-A synthase|synthase]] || 1 subfamily, 1 gene || [[Thromboxane-A synthase|CYP5A1]] ||
| '''CYP5''' || [[thromboxane]] A<sub>2</sub> [[thromboxane-A synthase|synthase]] || 1 subfamily, 1 gene || [[Thromboxane-A synthase|CYP5A1]] ||
|-
|-
| '''CYP7''' || [[bile acid]] biosynthesis 7-alpha hydroxylase of steroid nucleus || 2 subfamilies, 2 genes || [[CYP7A1]], [[CYP7B1]] ||
| '''CYP7''' || [[bile acid]] biosynthesis 7-alpha hydroxylase of steroid nucleus || 2 subfamilies, 2 genes || [[CYP7A1]], [[CYP7B1]] ||
|-
|-
| '''CYP8''' || ''varied'' || 2 subfamilies, 2 genes || [[CYP8A1]] ([[prostacyclin]] synthase), [[CYP8B1]] (bile acid biosynthesis) ||
| '''CYP8''' || ''varied'' || 2 subfamilies, 2 genes || [[CYP8A1]] ([[prostacyclin]] synthase), [[CYP8B1]] (bile acid biosynthesis) ||
|-
|-
| '''CYP11''' || [[steroid]] biosynthesis || 2 subfamilies, 3 genes || [[CYP11A1]], [[CYP11B1]], [[CYP11B2]] ||
| '''CYP11''' || [[steroid]] biosynthesis || 2 subfamilies, 3 genes || [[CYP11A1]], [[CYP11B1]], [[CYP11B2]] ||
|-
|-
| '''CYP17''' || [[steroid]] biosynthesis, 17-alpha hydroxylase || 1 subfamily, 1 gene || [[CYP17A1]] ||
| '''CYP17''' || [[steroid]] biosynthesis, 17-alpha hydroxylase || 1 subfamily, 1 gene || [[CYP17A1]] ||
|-
|-
| '''CYP19''' || [[steroid]] biosynthesis: [[aromatase]] synthesizes [[estrogen]] || 1 subfamily, 1 gene || [[CYP19A1]] ||
| '''CYP19''' || [[steroid]] biosynthesis: [[aromatase]] synthesizes [[estrogen]] || 1 subfamily, 1 gene || [[CYP19A1]] ||
|-
|-
| '''CYP20''' || unknown function || 1 subfamily, 1 gene || [[CYP20A1]] ||
| '''CYP20''' || unknown function || 1 subfamily, 1 gene || [[CYP20A1]] ||
|-
|-
| '''CYP21''' || [[steroid]] biosynthesis || 1 subfamilies, 1 gene, 1 pseudogene || [[CYP21A2]] || [[CYP21A1P]]
| '''CYP21''' || [[steroid]] biosynthesis || 1 subfamilies, 1 gene, 1 pseudogene || [[CYP21A2]] || [[CYP21A1P]]
|-
|-
| '''CYP24''' || [[vitamin D]] degradation || 1 subfamily, 1 gene || [[CYP24A1]] ||
| '''CYP24''' || [[vitamin D]] degradation || 1 subfamily, 1 gene || [[CYP24A1]] ||
|-
|-
| '''CYP26''' || [[retinoic acid]] hydroxylase || 3 subfamilies, 3 genes || [[CYP26A1]], [[CYP26B1]], [[CYP26C1]] ||
| '''[[CYP26]]''' || [[retinoic acid]] hydroxylase || 3 subfamilies, 3 genes || [[CYP26A1]], [[CYP26B1]], [[CYP26C1]] ||
|-
|-
| '''CYP27''' || ''varied'' || 3 subfamilies, 3 genes || [[CYP27A1]] ([[bile acid]] biosynthesis), [[CYP27B1]] (vitamin D<sub>3</sub> 1-alpha hydroxylase, activates vitamin D<sub>3</sub>), [[CYP27C1]] (unknown function) ||
| '''CYP27''' || ''varied'' || 3 subfamilies, 3 genes || [[CYP27A1]] ([[bile acid]] biosynthesis), [[CYP27B1]] (vitamin D<sub>3</sub> 1-alpha hydroxylase, activates vitamin D<sub>3</sub>), [[CYP27C1]] (vitamin A1 to A2) ||
|-
|-
| '''CYP39''' || 7-alpha hydroxylation of 24-hydroxycholesterol || 1 subfamily, 1 gene || [[CYP39A1]] ||
| '''CYP39''' || 7-alpha hydroxylation of 24-hydroxycholesterol || 1 subfamily, 1 gene || [[CYP39A1]] ||
|-
|-
| '''CYP46''' || [[cholesterol]] 24-hydroxylase || 1 subfamily, 1 gene, 1 pseudogene || [[CYP46A1]] || CYP46A4P
| '''CYP46''' || [[cholesterol]] 24-hydroxylase || 1 subfamily, 1 gene, 1 pseudogene || [[CYP46A1]] || CYP46A4P
|-
|-
| '''CYP51''' || [[cholesterol]] biosynthesis || 1 subfamily, 1 gene, 3 pseudogenes || [[CYP51A1]] ([[lanosterol]] 14-alpha demethylase) || CYP51P1, CYP51P2, CYP51P3
| '''CYP51''' || [[cholesterol]] biosynthesis || 1 subfamily, 1 gene, 3 pseudogenes || [[CYP51A1]] ([[lanosterol]] 14-alpha demethylase) || CYP51P1, CYP51P2, CYP51P3
|}
|}


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=== Animals ===
=== Animals ===
Animals often have more CYP genes than do humans. Reported numbers range from 35 genes in the sponge ''[[Amphimedon queenslandica]]'' to 235 genes in the cephalochordate ''[[Branchiostoma floridae]]''.<ref name="pmid23297357">{{cite journal | vauthors = Nelson DR, Goldstone JV, Stegeman JJ | title = The cytochrome P450 genesis locus: the origin and evolution of animal cytochrome P450s | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 368 | issue = 1612 | pages = 20120474 | date = February 2013 | pmid = 23297357 | pmc = 3538424 | doi = 10.1098/rstb.2012.0474 }}</ref> [[Mice]] have genes for 101 CYPs, and [[sea urchin]]s have even more (perhaps as many as 120 genes).<ref name="pmid17097629">{{cite journal | vauthors = Goldstone JV, Hamdoun A, Cole BJ, Howard-Ashby M, Nebert DW, Scally M, Dean M, Epel D, Hahn ME, Stegeman JJ | display-authors = 6 | title = The chemical defensome: environmental sensing and response genes in the Strongylocentrotus purpuratus genome | journal = Developmental Biology | volume = 300 | issue = 1 | pages = 366–384 | date = December 2006 | pmid = 17097629 | pmc = 3166225 | doi = 10.1016/j.ydbio.2006.08.066 }}</ref>
Other animals often have more P450 genes than humans do. Reported numbers range from 35 genes in the sponge ''[[Amphimedon queenslandica]]'' to 235 genes in the cephalochordate ''[[Branchiostoma floridae]]''.<ref name="pmid23297357">{{cite journal | vauthors = Nelson DR, Goldstone JV, Stegeman JJ | title = The cytochrome P450 genesis locus: the origin and evolution of animal cytochrome P450s | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 368 | issue = 1612 | pages = 20120474 | date = February 2013 | pmid = 23297357 | pmc = 3538424 | doi = 10.1098/rstb.2012.0474 }}</ref> [[Mice]] have genes for 101 P450s, and [[sea urchin]]s have even more (perhaps as many as 120 genes).<ref name="pmid17097629">{{cite journal | vauthors = Goldstone JV, Hamdoun A, Cole BJ, Howard-Ashby M, Nebert DW, Scally M, Dean M, Epel D, Hahn ME, Stegeman JJ | display-authors = 6 | title = The chemical defensome: environmental sensing and response genes in the Strongylocentrotus purpuratus genome | journal = Developmental Biology | volume = 300 | issue = 1 | pages = 366–384 | date = December 2006 | pmid = 17097629 | pmc = 3166225 | doi = 10.1016/j.ydbio.2006.08.066 }}</ref>
Most CYP enzymes are presumed to have monooxygenase activity, as is the case for most mammalian CYPs that have been investigated (except for, e.g., [[aromatase|CYP19]] and [[Thromboxane-A synthase|CYP5]]). [[Gene]] and [[genome sequencing]] is far outpacing [[biochemical]] characterization of enzymatic function, though many genes with close [[homology (biology)|homology]] to CYPs with known function have been found, giving clues to their functionality.
Most CYP enzymes are presumed to have monooxygenase activity, as is the case for most mammalian CYPs that have been investigated (except for, e.g., [[aromatase|CYP19]] and [[Thromboxane-A synthase|CYP5]]). [[Gene]] and [[genome sequencing]] is far outpacing [[biochemical]] characterization of enzymatic function, though many genes with close [[homology (biology)|homology]] to CYPs with known function have been found, giving clues to their functionality.


The classes of CYPs most often investigated in non-human animals are those either involved in [[developmental biology|development]] (e.g., [[retinoic acid]] or [[hormone]] metabolism) or involved in the metabolism of toxic compounds (such as [[heterocyclic amine]]s or [[polyaromatic hydrocarbons]]). Often there are differences in [[gene regulation]] or [[enzyme function]] of CYPs in related animals that explain observed differences in susceptibility to toxic compounds (ex. canines' inability to metabolize xanthines such as caffeine). Some drugs undergo metabolism in both species via different enzymes, resulting in different metabolites, while other drugs are metabolized in one species but excreted unchanged in another species. For this reason, one species's reaction to a substance is not a reliable indication of the substance's effects in humans. A species of Sonoran Desert Drosophila that uses an upregulated expression of the [[CYP28A1]] gene for detoxification of cacti rot is ''[[Drosophila mettleri]]''. Flies of this species have adapted an upregulation of this gene due to exposure of high levels of alkaloids in host plants.
The classes of P450s most often investigated in non-human animals are those either involved in [[developmental biology|development]] (e.g., [[retinoic acid]] or [[hormone]] metabolism) or involved in the metabolism of toxic compounds (such as [[heterocyclic amine]]s or [[polyaromatic hydrocarbons]]). Often there are differences in [[gene regulation]] or [[enzyme function]] of P450s in related animals that explain observed differences in susceptibility to toxic compounds (ex. canines' inability to metabolize xanthines such as caffeine). Some drugs undergo metabolism in both species via different enzymes, resulting in different metabolites, while other drugs are metabolized in one species but excreted unchanged in another species. For this reason, one species's reaction to a substance is not a reliable indication of the substance's effects in humans. A species of Sonoran Desert Drosophila that uses an upregulated expression of the [[CYP28A1]] gene for detoxification of cacti rot is ''[[Drosophila mettleri]]''. Flies of this species have adapted an upregulation of this gene due to exposure of high levels of alkaloids in host plants.


CYPs have been extensively examined in [[mice]], [[rat]]s, [[dog]]s, and less so in [[zebrafish]], in order to facilitate use of these [[model organisms]] in [[drug discovery]] and [[toxicology]]. Recently CYPs have also been discovered in avian species, in particular turkeys, that may turn out to be a useful model for cancer research in humans.<ref name="pmid20462619">{{cite journal | vauthors = Rawal S, Kim JE, Coulombe R | title = Aflatoxin B1 in poultry: toxicology, metabolism and prevention | journal = Research in Veterinary Science | volume = 89 | issue = 3 | pages = 325–331 | date = December 2010 | pmid = 20462619 | doi = 10.1016/j.rvsc.2010.04.011 }}</ref> [[CYP1A5]] and [[CYP3A37]] in turkeys were found to be very similar to the human [[CYP1A2]] and [[CYP3A4]] respectively, in terms of their kinetic properties as well as in the metabolism of aflatoxin B1.<ref name="pmid21616088">{{cite journal | vauthors = Rawal S, Coulombe RA | title = Metabolism of aflatoxin B1 in turkey liver microsomes: the relative roles of cytochromes P450 1A5 and 3A37 | journal = Toxicology and Applied Pharmacology | volume = 254 | issue = 3 | pages = 349–354 | date = August 2011 | pmid = 21616088 | doi = 10.1016/j.taap.2011.05.010 }}</ref>
P450s have been extensively examined in [[mice]], [[rat]]s, [[dog]]s, and less so in [[zebrafish]], in order to facilitate use of these [[model organisms]] in [[drug discovery]] and [[toxicology]]. Recently P450s have also been discovered in avian species, in particular turkeys, that may turn out to be a useful model for cancer research in humans.<ref name="pmid20462619">{{cite journal | vauthors = Rawal S, Kim JE, Coulombe R | title = Aflatoxin B1 in poultry: toxicology, metabolism and prevention | journal = Research in Veterinary Science | volume = 89 | issue = 3 | pages = 325–331 | date = December 2010 | pmid = 20462619 | doi = 10.1016/j.rvsc.2010.04.011 }}</ref> [[CYP1A5]] and [[CYP3A37]] in turkeys were found to be very similar to the human [[CYP1A2]] and [[CYP3A4]] respectively, in terms of their kinetic properties as well as in the metabolism of aflatoxin B1.<ref name="pmid21616088">{{cite journal | vauthors = Rawal S, Coulombe RA | title = Metabolism of aflatoxin B1 in turkey liver microsomes: the relative roles of cytochromes P450 1A5 and 3A37 | journal = Toxicology and Applied Pharmacology | volume = 254 | issue = 3 | pages = 349–354 | date = August 2011 | pmid = 21616088 | doi = 10.1016/j.taap.2011.05.010 }}</ref>


CYPs have also been heavily studied in [[insect]]s, often to understand [[pesticide resistance]]. For example, [[CYP6G1]] is linked to insecticide resistance in [[DDT]]-resistant ''[[Drosophila melanogaster]]''<ref>{{cite journal | vauthors = McCart C, Ffrench-Constant RH | title = Dissecting the insecticide-resistance- associated cytochrome P450 gene Cyp6g1 | journal = Pest Management Science | volume = 64 | issue = 6 | pages = 639–645 | date = June 2008 | pmid = 18338338 | doi = 10.1002/ps.1567 | s2cid = 41480564 | doi-access = free }}</ref> and [[CYP6M2]] in the mosquito [[malaria]] vector ''[[Anopheles gambiae]]'' is capable of directly metabolizing [[pyrethroids]].<ref name="Mosquito P450 activity">{{cite journal | vauthors = Ismail HM, O'Neill PM, Hong DW, Finn RD, Henderson CJ, Wright AT, Cravatt BF, Hemingway J, Paine MJ | display-authors = 6 | title = Pyrethroid activity-based probes for profiling cytochrome P450 activities associated with insecticide interactions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 49 | pages = 19766–19771 | date = December 2013 | pmid = 24248381 | pmc = 3856776 | doi = 10.1073/pnas.1320185110 | doi-access = free | bibcode = 2013PNAS..11019766I }}</ref>
CYPs have also been extensively studied in [[insect]]s, often to understand [[pesticide resistance]]. For example, [[CYP6G1]] is linked to insecticide resistance in [[DDT]]-resistant ''[[Drosophila melanogaster]]''<ref>{{cite journal | vauthors = McCart C, Ffrench-Constant RH | title = Dissecting the insecticide-resistance- associated cytochrome P450 gene Cyp6g1 | journal = Pest Management Science | volume = 64 | issue = 6 | pages = 639–645 | date = June 2008 | pmid = 18338338 | doi = 10.1002/ps.1567 | s2cid = 41480564 | doi-access = free }}</ref> and [[CYP6M2]] in the mosquito [[malaria]] vector ''[[Anopheles gambiae]]'' is capable of directly metabolizing [[pyrethroids]].<ref name="Mosquito P450 activity">{{cite journal | vauthors = Ismail HM, O'Neill PM, Hong DW, Finn RD, Henderson CJ, Wright AT, Cravatt BF, Hemingway J, Paine MJ | display-authors = 6 | title = Pyrethroid activity-based probes for profiling cytochrome P450 activities associated with insecticide interactions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 49 | pages = 19766–19771 | date = December 2013 | pmid = 24248381 | pmc = 3856776 | doi = 10.1073/pnas.1320185110 | doi-access = free | bibcode = 2013PNAS..11019766I }}</ref> Other cytochromes, such as those in ''Anopheles gambiae'', are under preliminary research for their potential role in [[pesticide resistance]], [[infectious disease]]s, and [[malaria]].<ref name="skor">{{cite journal | vauthors = Skorokhod O, Vostokova E, Gilardi G | title = The role of P450 enzymes in malaria and other vector-borne infectious diseases. | journal = Biofactors | volume = 50 | issue = 1 | pages = 16–32 | date = 2024 | pmid = 37555735 | doi = 10.1002/biof.1996 | doi-access = free }}</ref>


=== Microbial ===
=== Microbial ===
Microbial cytochromes P450 are often soluble enzymes and are involved in diverse metabolic processes. In bacteria the distribution of P450s is very variable with many bacteria having no identified P450s (e.g. ''E.coli''). Some bacteria, predominantly actinomycetes, have numerous P450s (e.g.,<ref>{{cite journal | vauthors = McLean KJ, Clift D, Lewis DG, Sabri M, Balding PR, Sutcliffe MJ, Leys D, Munro AW | display-authors = 6 | title = The preponderance of P450s in the Mycobacterium tuberculosis genome | journal = Trends in Microbiology | volume = 14 | issue = 5 | pages = 220–228 | date = May 2006 | pmid = 16581251 | doi = 10.1016/j.tim.2006.03.002 }}</ref><ref>{{cite journal | vauthors = Ikeda H, Ishikawa J, Hanamoto A, Shinose M, Kikuchi H, Shiba T, Sakaki Y, Hattori M, Omura S | display-authors = 6 | title = Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis | journal = Nature Biotechnology | volume = 21 | issue = 5 | pages = 526–531 | date = May 2003 | pmid = 12692562 | doi = 10.1038/nbt820 | doi-access = free }}</ref>). Those so far identified are generally involved in either biotransformation of xenobiotic compounds (e.g. [[Vitamin D3 dihydroxylase|CYP105A1]] from ''[[Streptomyces griseolus]]'' metabolizes [[sulfonylurea herbicide]]s to less toxic derivatives,<ref name="OKeefe-et-al-1988">{{cite journal | vauthors = O'Keefe DP, Romesser JA, Leto KJ | title=Identification of constitutive and herbicide inducible cytochromes P-450 in ''Streptomyces griseolus'' | journal=[[Archives of Microbiology]] | publisher=[[Springer Science+Business Media|Springer Science+Business]] | volume=149 | issue=5 | year=1988 | issn=0302-8933 | doi=10.1007/bf00425579 | pages=406–412 | bibcode=1988ArMic.149..406O | s2cid=35526991 }}</ref>) or are part of specialised metabolite biosynthetic pathways (e.g. [[CYP170B1]] catalyses production of the [[sesquiterpenoid]] albaflavenone in ''[[Streptomyces albus]]''<ref>{{cite journal | vauthors = Moody SC, Zhao B, Lei L, Nelson DR, Mullins JG, Waterman MR, Kelly SL, Lamb DC | display-authors = 6 | title = Investigating conservation of the albaflavenone biosynthetic pathway and CYP170 bifunctionality in streptomycetes | journal = The FEBS Journal | volume = 279 | issue = 9 | pages = 1640–1649 | date = May 2012 | pmid = 22151149 | doi = 10.1111/j.1742-4658.2011.08447.x | doi-access = free }}</ref>). Although no P450 has yet been shown to be essential in a microbe, the [[CYP105 family]] is highly conserved with a representative in every [[streptomycete]] genome sequenced so far.<ref>{{cite journal | vauthors = Moody SC, Loveridge EJ | title = CYP105-diverse structures, functions and roles in an intriguing family of enzymes in Streptomyces | journal = Journal of Applied Microbiology | volume = 117 | issue = 6 | pages = 1549–1563 | date = December 2014 | pmid = 25294646 | pmc = 4265290 | doi = 10.1111/jam.12662 }}</ref> Due to the solubility of bacterial P450 enzymes, they are generally regarded as easier to work with than the predominantly membrane bound eukaryotic P450s. This, combined with the remarkable chemistry they catalyse, has led to many studies using the [[heterologously expressed protein]]s in vitro. Few studies have investigated what P450s do in vivo, what the natural substrate(s) are and how P450s contribute to survival of the bacteria in the natural environment.Three examples that have contributed significantly to structural and mechanistic studies are listed here, but many different families exist.

Microbial cytochromes P450 are often soluble enzymes and are involved in diverse metabolic processes. In bacteria the distribution of P450s is very variable with many bacteria having no identified P450s (e.g. ''E.coli''). Some bacteria, predominantly actinomycetes, have numerous P450s (e.g.,<ref>{{cite journal | vauthors = McLean KJ, Clift D, Lewis DG, Sabri M, Balding PR, Sutcliffe MJ, Leys D, Munro AW | display-authors = 6 | title = The preponderance of P450s in the Mycobacterium tuberculosis genome | journal = Trends in Microbiology | volume = 14 | issue = 5 | pages = 220–228 | date = May 2006 | pmid = 16581251 | doi = 10.1016/j.tim.2006.03.002 }}</ref><ref>{{cite journal | vauthors = Ikeda H, Ishikawa J, Hanamoto A, Shinose M, Kikuchi H, Shiba T, Sakaki Y, Hattori M, Omura S | display-authors = 6 | title = Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis | journal = Nature Biotechnology | volume = 21 | issue = 5 | pages = 526–531 | date = May 2003 | pmid = 12692562 | doi = 10.1038/nbt820 | doi-access = free }}</ref>). Those so far identified are generally involved in either biotransformation of xenobiotic compounds (e.g. [[Vitamin D3 dihydroxylase|CYP105A1]] from ''[[Streptomyces griseolus]]'' metabolizes [[sulfonylurea herbicide]]s to less toxic derivatives,<ref name="OKeefe-et-al-1988">{{cite journal | vauthors = O'Keefe DP, Romesser JA, Leto KJ | title=Identification of constitutive and herbicide inducible cytochromes P-450 in ''Streptomyces griseolus'' | journal=[[Archives of Microbiology]] | publisher=[[Springer Science+Business Media|Springer Science+Business]] | volume=149 | issue=5 | year=1988 | issn=0302-8933 | doi=10.1007/bf00425579 | pages=406–412 | s2cid=35526991 }}</ref>) or are part of specialised metabolite biosynthetic pathways (e.g. [[CYP170B1]] catalyses production of the [[sesquiterpenoid]] albaflavenone in ''[[Streptomyces albus]]''<ref>{{cite journal | vauthors = Moody SC, Zhao B, Lei L, Nelson DR, Mullins JG, Waterman MR, Kelly SL, Lamb DC | display-authors = 6 | title = Investigating conservation of the albaflavenone biosynthetic pathway and CYP170 bifunctionality in streptomycetes | journal = The FEBS Journal | volume = 279 | issue = 9 | pages = 1640–1649 | date = May 2012 | pmid = 22151149 | doi = 10.1111/j.1742-4658.2011.08447.x | doi-access = free }}</ref>). Although no P450 has yet been shown to be essential in a microbe, the [[CYP105 family]] is highly conserved with a representative in every [[streptomycete]] genome sequenced so far.<ref>{{cite journal | vauthors = Moody SC, Loveridge EJ | title = CYP105-diverse structures, functions and roles in an intriguing family of enzymes in Streptomyces | journal = Journal of Applied Microbiology | volume = 117 | issue = 6 | pages = 1549–1563 | date = December 2014 | pmid = 25294646 | pmc = 4265290 | doi = 10.1111/jam.12662 }}</ref> Due to the solubility of bacterial P450 enzymes, they are generally regarded as easier to work with than the predominantly membrane bound eukaryotic P450s. This, combined with the remarkable chemistry they catalyse, has led to many studies using the [[heterologously expressed protein]]s in vitro. Few studies have investigated what P450s do in vivo, what the natural substrate(s) are and how P450s contribute to survival of the bacteria in the natural environment.Three examples that have contributed significantly to structural and mechanistic studies are listed here, but many different families exist.

* [[Cytochrome P450 cam]] (CYP101A1) originally from ''[[Pseudomonas putida]]'' has been used as a model for many cytochromes P450 and was the first cytochrome P450 three-dimensional protein structure solved by X-ray crystallography. This enzyme is part of a camphor-hydroxylating catalytic cycle consisting of two electron transfer steps from [[putidaredoxin]], a 2Fe-2S cluster-containing protein cofactor.
* [[Cytochrome P450 cam]] (CYP101A1) originally from ''[[Pseudomonas putida]]'' has been used as a model for many cytochromes P450 and was the first cytochrome P450 three-dimensional protein structure solved by X-ray crystallography. This enzyme is part of a camphor-hydroxylating catalytic cycle consisting of two electron transfer steps from [[putidaredoxin]], a 2Fe-2S cluster-containing protein cofactor.
* [[Cytochrome P450 eryF]] (CYP107A1) originally from the actinomycete bacterium ''[[Saccharopolyspora erythraea]]'' is responsible for the biosynthesis of the [[antibiotic]] [[erythromycin]] by C6-hydroxylation of the macrolide 6-deoxyerythronolide B.
* [[Cytochrome P450 eryF]] (CYP107A1) originally from the actinomycete bacterium ''[[Saccharopolyspora erythraea]]'' is responsible for the biosynthesis of the [[antibiotic]] [[erythromycin]] by C6-hydroxylation of the macrolide 6-deoxyerythronolide B.
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=== Fungi ===
=== Fungi ===


The commonly used [[Antifungal drug#Imidazole.2C triazole.2C and thiazole antifungals|azole]] class antifungal drugs work by inhibition of the fungal [[cytochrome P450 14α-demethylase]]. This interrupts the conversion of [[lanosterol]] to [[ergosterol]], a component of the fungal cell membrane. (This is useful only because humans' P450 have a different sensitivity; this is how this class of [[antifungals]] work.)<ref name="pmid2091733">{{cite journal | vauthors = Vanden Bossche H, Marichal P, Gorrens J, Coene MC | title = Biochemical basis for the activity and selectivity of oral antifungal drugs | journal = British Journal of Clinical Practice. Supplement | volume = 71 | pages = 41–46 | date = September 1990 | pmid = 2091733 }}</ref>
The commonly used [[Antifungal drug#Imidazole, triazole, and thiazole antifungals|azole]] class of antifungal drugs works by inhibition of the fungal [[cytochrome P450 14α-demethylase]].<ref name="pmid2091733">{{cite journal | vauthors = Vanden Bossche H, Marichal P, Gorrens J, Coene MC | title = Biochemical basis for the activity and selectivity of oral antifungal drugs | journal = British Journal of Clinical Practice. Supplement | volume = 71 | pages = 41–46 | date = September 1990 | pmid = 2091733 }}</ref>{{better source needed|date=March 2024}}

Significant research is ongoing into fungal P450s, as a number of fungi are [[Pathogenic fungi|pathogenic]] to humans (such as [[Candida (fungus)|Candida]] [[yeast]] and [[Aspergillus]]) and to plants.

''[[Cunninghamella elegans]]'' is a candidate for use as a model for mammalian drug metabolism.


=== Plants ===
=== Plants ===


Cytochromes P450 are involved in a variety of processes of plant growth, development, and defense. It is estimated that CYP P450 genes comprises approximately 1% of the plant genome.<ref>{{cite journal | vauthors = Mizutani M | title = Impacts of diversification of cytochrome P450 on plant metabolism | journal = Biological & Pharmaceutical Bulletin | volume = 35 | issue = 6 | pages = 824–832 | date = 2012 | pmid = 22687470 | doi = 10.1248/bpb.35.824 }}</ref><ref>{{cite journal | vauthors = Mizutani M, Sato F | title = Unusual P450 reactions in plant secondary metabolism | journal = Archives of Biochemistry and Biophysics | volume = 507 | issue = 1 | pages = 194–203 | date = March 2011 | pmid = 20920462 | doi = 10.1016/j.abb.2010.09.026 | series = P450 Catalysis Mechanisms }}</ref> These enzymes lead to various [[fatty acid]] conjugates, [[plant hormone]]s, [[secondary metabolite]]s, [[lignin]]s, and a variety of defensive compounds.<ref>{{cite journal | vauthors = Schuler MA, Werck-Reichhart D | title = Functional genomics of P450s | journal = Annual Review of Plant Biology | volume = 54 | issue = 1 | pages = 629–667 | date = 2003-01-01 | pmid = 14503006 | doi = 10.1146/annurev.arplant.54.031902.134840 }}</ref>
Cytochromes P450 are involved in a variety of processes of plant growth, development, and defense. It is estimated that P450 genes make up approximately 1% of the plant genome.<ref name="Impacts of diversification of cytoc">{{cite journal | vauthors = Mizutani M | title = Impacts of diversification of cytochrome P450 on plant metabolism | journal = Biological & Pharmaceutical Bulletin | volume = 35 | issue = 6 | pages = 824–832 | date = 2012 | pmid = 22687470 | doi = 10.1248/bpb.35.824 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mizutani M, Sato F | title = Unusual P450 reactions in plant secondary metabolism | journal = Archives of Biochemistry and Biophysics | volume = 507 | issue = 1 | pages = 194–203 | date = March 2011 | pmid = 20920462 | doi = 10.1016/j.abb.2010.09.026 | series = P450 Catalysis Mechanisms }}</ref> These enzymes lead to various [[fatty acid]] conjugates, [[plant hormone]]s, [[secondary metabolite]]s, [[lignin]]s, and a variety of defensive compounds.<ref>{{cite journal | vauthors = Schuler MA, Werck-Reichhart D | title = Functional genomics of P450s | journal = Annual Review of Plant Biology | volume = 54 | issue = 1 | pages = 629–667 | date = 2003-01-01 | pmid = 14503006 | doi = 10.1146/annurev.arplant.54.031902.134840 }}</ref>


Cytochrome P450s play an important role in plant defense– involvement in phytoalexin biosynthesis, hormone metabolism, and biosynthesis of diverse secondary metabolites.<ref>{{Cite journal | vauthors = Xu J, Wang X, Guo W |date=2015-09-01 |title=The cytochrome P450 superfamily: Key players in plant development and defense |journal=Journal of Integrative Agriculture |language=en |volume=14 |issue=9 |pages=1673–1686 |doi=10.1016/S2095-3119(14)60980-1 |issn=2095-3119}}</ref> The expression of cytochrome p450 genes is regulated in response to environmental stresses indicative of a critical role in plant defense mechanisms.<ref>{{cite journal | vauthors = Heitz T, Widemann E, Lugan R, Miesch L, Ullmann P, Désaubry L, Holder E, Grausem B, Kandel S, Miesch M, Werck-Reichhart D, Pinot F | display-authors = 6 | title = Cytochromes P450 CYP94C1 and CYP94B3 catalyze two successive oxidation steps of plant hormone Jasmonoyl-isoleucine for catabolic turnover | journal = The Journal of Biological Chemistry | volume = 287 | issue = 9 | pages = 6296–6306 | date = February 2012 | pmid = 22215670 | pmc = 3307330 | doi = 10.1074/jbc.M111.316364 }}</ref>
Cytochromes P450 play an important role in plant defense– involvement in phytoalexin biosynthesis, hormone metabolism, and biosynthesis of diverse secondary metabolites.<ref>{{Cite journal | vauthors = Xu J, Wang X, Guo W |date=2015-09-01 |title=The cytochrome P450 superfamily: Key players in plant development and defense |journal=Journal of Integrative Agriculture |language=en |volume=14 |issue=9 |pages=1673–1686 |doi=10.1016/S2095-3119(14)60980-1 |issn=2095-3119|doi-access=free }}</ref> The expression of cytochrome p450 genes is regulated in response to environmental stresses indicative of a critical role in plant defense mechanisms.<ref>{{cite journal | vauthors = Heitz T, Widemann E, Lugan R, Miesch L, Ullmann P, Désaubry L, Holder E, Grausem B, Kandel S, Miesch M, Werck-Reichhart D, Pinot F | display-authors = 6 | title = Cytochromes P450 CYP94C1 and CYP94B3 catalyze two successive oxidation steps of plant hormone Jasmonoyl-isoleucine for catabolic turnover | journal = The Journal of Biological Chemistry | volume = 287 | issue = 9 | pages = 6296–6306 | date = February 2012 | pmid = 22215670 | pmc = 3307330 | doi = 10.1074/jbc.M111.316364 | doi-access = free }}</ref>


Phytoalexins have shown to be important in plant defense mechanisms as they are antimicrobial compounds produced by plants in response to plant pathogens. Phytoalexins are not pathogen-specific, but rather plant-specific; each plant has its own unique set of phytoalexins. However, they can still attack a wide range of different pathogens. Arabidopsis is a plant closely related to cabbage and mustard and produces the phytoalexin camalexin. Camalexin originates from tryptophan and its biosynthesis involves five cytochrome P450 enzymes. The five cytochrome P450 enzymes include CYP79B2, CYP79B3, CYP71A12, CYP71A13, and CYP71B15. The first step of camalexin biosynthesis produces indole-3-acetaldoxime (IAOx) from tryptophan and is catalyzed by either CYP79B2 or CYP79B3. IAOx is then immediately converted to indole-3-acetonitrile (IAN) and is controlled by either CYP71A13 or its homolog CYP71A12. The last two steps of the biosynthesis pathway of camalexin are catalyzed by CYP71B15. In these steps, indole-3-carboxylic acid (DHCA) is formed from cysteine-indole-3-acetonitrile (Cys(IAN)) followed by the biosynthesis of camalexin. There are some intermediate steps within the pathway that remain unclear, but it is well understood that cytochrome P450 is pivotal in camalexin biosynthesis and that this phytoalexin plays a major role in plant defense mechanisms.<ref>{{cite journal | vauthors = Pandian BA, Sathishraj R, Djanaguiraman M, Prasad PV, Jugulam M | title = Role of Cytochrome P450 Enzymes in Plant Stress Response | journal = Antioxidants | volume = 9 | issue = 5 | pages = 454 | date = May 2020 | pmid = 32466087 | doi = 10.3390/antiox9050454 }}</ref>
Phytoalexins have shown to be important in plant defense mechanisms as they are antimicrobial compounds produced by plants in response to plant pathogens. Phytoalexins are not pathogen-specific, but rather plant-specific; each plant has its own unique set of phytoalexins. However, they can still attack a wide range of different pathogens. Arabidopsis is a plant closely related to cabbage and mustard and produces the phytoalexin camalexin. Camalexin originates from tryptophan and its biosynthesis involves five cytochrome P450 enzymes. The five cytochrome P450 enzymes include CYP79B2, CYP79B3, CYP71A12, CYP71A13, and CYP71B15. The first step of camalexin biosynthesis produces indole-3-acetaldoxime (IAOx) from tryptophan and is catalyzed by either CYP79B2 or CYP79B3. IAOx is then immediately converted to indole-3-acetonitrile (IAN) and is controlled by either CYP71A13 or its homolog CYP71A12. The last two steps of the biosynthesis pathway of camalexin are catalyzed by CYP71B15. In these steps, indole-3-carboxylic acid (DHCA) is formed from cysteine-indole-3-acetonitrile (Cys(IAN)) followed by the biosynthesis of camalexin. There are some intermediate steps within the pathway that remain unclear, but it is well understood that cytochrome P450 is pivotal in camalexin biosynthesis and that this phytoalexin plays a major role in plant defense mechanisms.<ref>{{cite journal | vauthors = Pandian BA, Sathishraj R, Djanaguiraman M, Prasad PV, Jugulam M | title = Role of Cytochrome P450 Enzymes in Plant Stress Response | journal = Antioxidants | volume = 9 | issue = 5 | pages = 454 | date = May 2020 | pmid = 32466087 | doi = 10.3390/antiox9050454 | pmc = 7278705 | doi-access = free }}</ref>


Cytochrome P450s are largely responsible for the synthesis of the jasmonic acid (JA), a common hormonal defenses against abiotic and biotic stresses for plant cells. For example, a P450, CYP74A is involved in the dehydration reaction to produce an insatiable allene oxide from hydroperoxide.<ref>{{Cite web |title=Canvas Login |url=https://login.canvas.uw.edu/wayf |access-date=2022-06-07 |website=login.canvas.uw.edu}}</ref> JA chemical reactions are critical in the presence of biotic stresses that can be caused by plant wounding, specifically shown in the plant, Arabidopsis. As a prohormone, jasmonic acid must be converted to the JA-isoleucine (JA-Ile) conjugate by JAR1 catalysation in order to be considered activated. Then, JA-Ile synthesis leads to the assembly of the co-receptor complex comprised of COI1 and several JAZ proteins. Under low JA-Ile conditions, the JAZ protein components act as transcriptional repressors to suppress downstream JA genes. However, under adequate JA-Ile conditions, the JAZ proteins are ubiquitinated and undergo degradation through the 26S proteasome, resulting in functional downstream effects. Furthermore, several CYP94s (CYP94C1 and CYP94B3) are related to JA-Ile turnover and show that JA-Ile oxidation status impacts plant signaling in a catabolic manner.<ref>{{cite journal | vauthors = Mizutani M | title = Impacts of diversification of cytochrome P450 on plant metabolism | journal = Biological & Pharmaceutical Bulletin | volume = 35 | issue = 6 | pages = 824–832 | date = 2012 | pmid = 22687470 | doi = 10.1248/bpb.35.824 }}</ref> Cytochrome P450 hormonal regulation in response to extracellular and intracellular stresses is critical for proper plant defense response. This has been proven through thorough analysis of various CYP P450s in jasmonic acid and phytoalexin pathways.
Cytochromes P450 are largely responsible for the synthesis of the jasmonic acid (JA), a common hormonal defenses against abiotic and biotic stresses for plant cells. For example, a P450, CYP74A is involved in the dehydration reaction to produce an insatiable allene oxide from hydroperoxide.<ref>{{Cite web |title=Canvas Login |url=https://login.canvas.uw.edu/wayf |access-date=2022-06-07 |website=login.canvas.uw.edu}}</ref> JA chemical reactions are critical in the presence of biotic stresses that can be caused by plant wounding, specifically shown in the plant, Arabidopsis. As a prohormone, jasmonic acid must be converted to the JA-isoleucine (JA-Ile) conjugate by JAR1 catalysation in order to be considered activated. Then, JA-Ile synthesis leads to the assembly of the co-receptor complex compo`sed of COI1 and several JAZ proteins. Under low JA-Ile conditions, the JAZ protein components act as transcriptional repressors to suppress downstream JA genes. However, under adequate JA-Ile conditions, the JAZ proteins are ubiquitinated and undergo degradation through the 26S proteasome, resulting in functional downstream effects. Furthermore, several CYP94s (CYP94C1 and CYP94B3) are related to JA-Ile turnover and show that JA-Ile oxidation status impacts plant signaling in a catabolic manner.<ref name="Impacts of diversification of cytoc"/> Cytochrome P450 hormonal regulation in response to extracellular and intracellular stresses is critical for proper plant defense response. This has been proven through thorough analysis of various CYP P450s in jasmonic acid and phytoalexin pathways.


[[Cytochrome P450 aromatic O-demethylase]], which is made of two distinct promiscuous parts: a cytochrome P450 protein (GcoA) and three domain reductase, is significant for its ability to convert Lignin, the aromatic biopolymer common in plant cell walls, into renewable carbon chains in a catabolic set of reactions. In short, it is a facilitator of a critical step in Lignin conversion.
[[Cytochrome P450 aromatic O-demethylase]], which is made of two distinct promiscuous parts: a cytochrome P450 protein (GcoA) and three domain reductase, is significant for its ability to convert Lignin, the aromatic biopolymer common in plant cell walls, into renewable carbon chains in a catabolic set of reactions. In short, it is a facilitator of a critical step in Lignin conversion.

== P450s in biotechnology ==

The remarkable reactivity and substrate promiscuity of P450s have long attracted the attention of chemists.<ref name="pmid17216026">{{cite journal | vauthors = Chefson A, Auclair K | title = Progress towards the easier use of P450 enzymes | journal = Molecular bioSystems | volume = 2 | issue = 10 | pages = 462–469 | date = October 2006 | pmid = 17216026 | doi = 10.1039/b607001a | author-link2 = Karine Auclair }}</ref> Recent progress towards realizing the potential of using P450s towards difficult oxidations have included: (i) eliminating the need for natural co-factors by replacing them with inexpensive peroxide containing molecules,<ref name="pmid16671126">{{cite journal | vauthors = Chefson A, Zhao J, Auclair K | title = Replacement of natural cofactors by selected hydrogen peroxide donors or organic peroxides results in improved activity for CYP3A4 and CYP2D6 | journal = Chembiochem | volume = 7 | issue = 6 | pages = 916–919 | date = June 2006 | pmid = 16671126 | doi = 10.1002/cbic.200600006 | s2cid = 39329433 }}</ref> (ii) exploring the compatibility of P450s with organic solvents,<ref name="pmid17526062">{{cite journal | vauthors = Chefson A, Auclair K | title = CYP3A4 activity in the presence of organic cosolvents, ionic liquids, or water-immiscible organic solvents | journal = Chembiochem | volume = 8 | issue = 10 | pages = 1189–1197 | date = July 2007 | pmid = 17526062 | doi = 10.1002/cbic.200700128 | s2cid = 11845235 }}</ref> and (iii) the use of small, non-chiral auxiliaries to predictably direct P450 oxidation.{{Citation needed|date=April 2011}}


==InterPro subfamilies==
==InterPro subfamilies==
{{Cleanup|section|reason=broken links; fragmented paragraph.|date=September 2016}}
{{Cleanup|section|reason=broken links; fragmented paragraph.|date=September 2016}}
[[InterPro]] subfamilies:
[[InterPro]] subfamilies:
*Cytochrome P450, B-class {{InterPro|IPR002397}}
* Cytochrome P450, B-class {{InterPro|IPR002397}}
*Cytochrome P450, mitochondrial {{InterPro|IPR002399}}
* Cytochrome P450, mitochondrial {{InterPro|IPR002399}}
*Cytochrome P450, E-class, group I {{InterPro|IPR002401}}
* Cytochrome P450, E-class, group I {{InterPro|IPR002401}}
*Cytochrome P450, E-class, group II {{InterPro|IPR002402}}
* Cytochrome P450, E-class, group II {{InterPro|IPR002402}}
*Cytochrome P450, E-class, group IV {{InterPro|IPR002403}}
* Cytochrome P450, E-class, group IV {{InterPro|IPR002403}}
*[[Aromatase]]
* [[Aromatase]]
Clozapine, imipramine, paracetamol, phenacetin Heterocyclic aryl amines
Clozapine, imipramine, paracetamol, phenacetin Heterocyclic aryl amines
Inducible and CYP1A2 5-10% deficient
Inducible and CYP1A2 5-10% deficient
oxidize uroporphyrinogen to uroporphyrin (CYP1A2) in heme metabolism, but they may have additional undiscovered endogenous substrates.
oxidize uroporphyrinogen to uroporphyrin (CYP1A2) in heme metabolism, but they may have additional undiscovered endogenous substrates.
are inducible by some polycyclic hydrocarbons, some of which are found in cigarette smoke and charred food.
are inducible by some polycyclic hydrocarbons, some of which are found in cigarette smoke and charred food.


These enzymes are of interest, because in assays, they can activate compounds to carcinogens.
These enzymes are of interest, because in assays, they can activate compounds to carcinogens.
High levels of CYP1A2 have been linked to an increased risk of colon cancer. Since the 1A2 enzyme can be induced by cigarette smoking, this links smoking with colon cancer.<ref>{{cite journal | vauthors = Petros WP, Younis IR, Ford JN, Weed SA | title = Effects of tobacco smoking and nicotine on cancer treatment | journal = Pharmacotherapy | volume = 32 | issue = 10 | pages = 920–931 | date = October 2012 | pmid = 23033231 | pmc = 3499669 | doi = 10.1002/j.1875-9114.2012.01117 }}</ref>
High levels of CYP1A2 have been linked to an increased risk of colon cancer. Since the 1A2 enzyme can be induced by cigarette smoking, this links smoking with colon cancer.<ref>{{cite journal | vauthors = Petros WP, Younis IR, Ford JN, Weed SA | title = Effects of tobacco smoking and nicotine on cancer treatment | journal = Pharmacotherapy | volume = 32 | issue = 10 | pages = 920–931 | date = October 2012 | pmid = 23033231 | pmc = 3499669 | doi = 10.1002/j.1875-9114.2012.01117 }}</ref>


== See also ==
== See also ==
{{Portal|Biology}}
* [[Steroidogenic enzyme]]
* [[Steroidogenic enzyme]]
* [[Cytochrome P450 oxidoreductase deficiency]]
* [[Cytochrome P450 oxidoreductase deficiency]]
Line 240: Line 235:
* {{Cite web|url=https://home.ccr.cancer.gov/metabolism/mab1.htm|title=Cytochrome P450 Mediated Drug and Carcinogen Metabolism using Monoclonal Antibodies|website=home.ccr.cancer.gov|access-date=2018-04-02}}
* {{Cite web|url=https://home.ccr.cancer.gov/metabolism/mab1.htm|title=Cytochrome P450 Mediated Drug and Carcinogen Metabolism using Monoclonal Antibodies|website=home.ccr.cancer.gov|access-date=2018-04-02}}
* {{cite journal | vauthors = Krausz KW, Goldfarb I, Buters JT, Yang TJ, Gonzalez FJ, Gelboin HV | title = Monoclonal antibodies specific and inhibitory to human cytochromes P450 2C8, 2C9, and 2C19 | journal = Drug Metabolism and Disposition | volume = 29 | issue = 11 | pages = 1410–1423 | date = November 2001 | pmid = 11602516 | url = http://dmd.aspetjournals.org/content/29/11/1410 }}
* {{cite journal | vauthors = Krausz KW, Goldfarb I, Buters JT, Yang TJ, Gonzalez FJ, Gelboin HV | title = Monoclonal antibodies specific and inhibitory to human cytochromes P450 2C8, 2C9, and 2C19 | journal = Drug Metabolism and Disposition | volume = 29 | issue = 11 | pages = 1410–1423 | date = November 2001 | pmid = 11602516 | url = http://dmd.aspetjournals.org/content/29/11/1410 }}
* {{cite journal | vauthors = Gonzalez FJ, Gelboin HV | title = Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins | journal = Drug Metabolism Reviews | volume = 26 | issue = 1-2 | pages = 165–183 | date = 1994 | pmid = 8082563 | doi = 10.3109/03602539409029789 }}
* {{cite journal | vauthors = Gonzalez FJ, Gelboin HV | title = Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins | journal = Drug Metabolism Reviews | volume = 26 | issue = 1–2 | pages = 165–183 | date = 1994 | pmid = 8082563 | doi = 10.3109/03602539409029789 }}
* {{cite journal | vauthors = Estabrook RW | title = A passion for P450s (rememberances of the early history of research on cytochrome P450) | journal = Drug Metabolism and Disposition | volume = 31 | issue = 12 | pages = 1461–1473 | date = December 2003 | pmid = 14625342 | doi = 10.1124/dmd.31.12.1461 }}
* {{cite journal | vauthors = Estabrook RW | title = A passion for P450s (Remembrances of the early history of research on cytochrome P450) | journal = Drug Metabolism and Disposition | volume = 31 | issue = 12 | pages = 1461–1473 | date = December 2003 | pmid = 14625342 | doi = 10.1124/dmd.31.12.1461 | s2cid = 43655270 }}
{{Refend}}
{{Refend}}


== External links ==
== External links ==
{{Commons category}}
{{Commons category}}
{{Portal|Biology}}
* {{cite web | vauthors = Degtyarenko K | url = http://www.icgeb.org/~p450srv/ | title = Directory of P450-containing Systems | date = 2009-01-09 | publisher = [[International Centre for Genetic Engineering and Biotechnology]] | access-date = 2009-02-10 | archive-url = https://web.archive.org/web/20160716081404/http://www.icgeb.org/~p450srv/ | archive-date = 2016-07-16 | url-status = dead }}
* {{cite web | vauthors = Degtyarenko K | url = http://www.icgeb.org/~p450srv/ | title = Directory of P450-containing Systems | date = 2009-01-09 | publisher = [[International Centre for Genetic Engineering and Biotechnology]] | access-date = 2009-02-10 | archive-url = https://web.archive.org/web/20160716081404/http://www.icgeb.org/~p450srv/ | archive-date = 2016-07-16 | url-status = dead }}
* {{cite web | vauthors = Flockhart DA | url = https://www.pharmvar.org/ | title = Human Cytochrome P450 (CYP) Allele Nomenclature Committee | date = 2008-09-04 | publisher = [[Karolinska Institutet]] | access-date = 2009-02-10}}
* {{cite web | vauthors = Flockhart DA | url = https://www.pharmvar.org/ | title = Human Cytochrome P450 (CYP) Allele Nomenclature Committee | date = 2008-09-04 | publisher = [[Karolinska Institutet]] | access-date = 2009-02-10}}
* {{cite web | vauthors = Preissner S | url = http://bioinformatics.charite.de/supercyp/ | title = Cytochrome P450 database | year = 2010 | publisher = Nucleic Acids Research }}
* {{cite web | vauthors = Preissner S | url = http://bioinformatics.charite.de/supercyp/ | title = Cytochrome P450 database | year = 2010 | publisher = Nucleic Acids Research | access-date = 2011-08-02 | archive-date = 2011-11-03 | archive-url = https://web.archive.org/web/20111103123642/http://bioinformatics.charite.de/supercyp/ | url-status = dead }}
* {{cite web | vauthors = Sigaroudi A, Vollbrecht H | url = http://www.kisch.ch/ | title = pharmacokinetic interaction table | year = 2019 | publisher = Sigaroudi & Vollbrecht }}
* {{cite web | vauthors = Sigaroudi A, Vollbrecht H | url = http://www.kisch.ch/ | title = pharmacokinetic interaction table | year = 2019 | publisher = Sigaroudi & Vollbrecht }}
* {{cite web | vauthors = Sim SC | url = http://medicine.iupui.edu/flockhart/ | title = Cytochrome P450 drug interaction table | year = 2007 | publisher = [[Indiana University-Purdue University Indianapolis]] | access-date = 2009-02-10}}
* {{cite web | vauthors = Sim SC | url = http://medicine.iupui.edu/flockhart/ | title = Cytochrome P450 drug interaction table | year = 2007 | publisher = [[Indiana University-Purdue University Indianapolis]] | access-date = 2009-02-10}}

Revision as of 06:12, 6 April 2024

Cytochrome P450
Structure of lanosterol 14α-demethylase (CYP51)
Identifiers
Symbolp450
PfamPF00067
InterProIPR001128
PROSITEPDOC00081
SCOP22cpp / SCOPe / SUPFAM
OPM superfamily39
OPM protein2bdm
CDDcd00302
Membranome265
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Cytochromes P450 (P450s or CYPs) are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases.[1][2][3] In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown, steroid hormone synthesis, drug metabolism, and the biosynthesis of defensive compounds, fatty acids, and hormones.[2] CYP450 enzymes convert xenobiotics into hydrophilic derivatives, which are more readily excreted. In almost all of the transformations that they catalyze, P450's affect hydroxylation.

P450 enzymes have been identified in all kingdoms of life: animals, plants, fungi, protists, bacteria, and archaea, as well as in viruses.[4] However, they are not omnipresent; for example, they have not been found in Escherichia coli.[3][5] As of 2018, more than 300,000 distinct CYP proteins are known.[6][7]

P450s are, in general, the terminal oxidase enzymes in electron transfer chains, broadly categorized as P450-containing systems. The term "P450" is derived from the spectrophotometric peak at the wavelength of the absorption maximum of the enzyme (450 nm) when it is in the reduced state and complexed with carbon monoxide. Most P450s require a protein partner to deliver one or more electrons to reduce the iron (and eventually molecular oxygen).

Nomenclature

Genes encoding P450 enzymes, and the enzymes themselves, are designated with the root symbol CYP for the superfamily, followed by a number indicating the gene family, a capital letter indicating the subfamily, and another numeral for the individual gene. The convention is to italicise the name when referring to the gene. For example, CYP2E1 is the gene that encodes the enzyme CYP2E1—one of the enzymes involved in paracetamol (acetaminophen) metabolism. The CYP nomenclature is the official naming convention, although occasionally CYP450 or CYP450 is used synonymously. These names should never be used as according to the nomenclature convention (as they denote a P450 in family number 450). However, some gene or enzyme names for P450s are also referred to by historical names (e.g. P450BM3 for CYP102A1) or functional names, denoting the catalytic activity and the name of the compound used as substrate. Examples include CYP5A1, thromboxane A2 synthase, abbreviated to TBXAS1 (ThromBoXane A2 Synthase 1), and CYP51A1, lanosterol 14-α-demethylase, sometimes unofficially abbreviated to LDM according to its substrate (Lanosterol) and activity (DeMethylation).[8]

The current nomenclature guidelines suggest that members of new CYP families share at least 40% amino-acid identity, while members of subfamilies must share at least 55% amino-acid identity. Nomenclature committees assign and track both base gene names (Cytochrome P450 Homepage Archived 2010-06-27 at the Wayback Machine) and allele names (CYP Allele Nomenclature Committee).[9][10]

Classification

Based on the nature of the electron transfer proteins, P450s can be classified into several groups:[11]

Microsomal P450 systems
in which electrons are transferred from NADPH via cytochrome P450 reductase (variously CPR, POR, or CYPOR). Cytochrome b5 (cyb5) can also contribute reducing power to this system after being reduced by cytochrome b5 reductase (CYB5R).
Mitochondrial P450 systems
which employ adrenodoxin reductase and adrenodoxin to transfer electrons from NADPH to P450.
Bacterial P450 systems
which employ a ferredoxin reductase and a ferredoxin to transfer electrons to P450.
CYB5R/cyb5/P450 systems
in which both electrons required by the CYP come from cytochrome b5.
FMN/Fd/P450 systems
originally found in Rhodococcus species, in which a FMN-domain-containing reductase is fused to the CYP.
P450 only systems
which do not require external reducing power. Notable ones include thromboxane synthase (CYP5), prostacyclin synthase (CYP8), and CYP74A (allene oxide synthase).

The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH), while the other oxygen atom is reduced to water:

RH + O2 + NADPH + H+ → ROH + H2O + NADP+

Many hydroxylation reactions (insertion of hydroxyl groups) use CYP enzymes.

Mechanism

The P450 catalytic cycle
The "Fe(V) intermediate" at the bottom left is a simplification: it is an Fe(IV) with a radical heme ligand.

Structure

The active site of cytochrome P450 contains a heme-iron center. The iron is tethered to the protein via a cysteine thiolate ligand. This cysteine and several flanking residues are highly conserved in known P450s, and have the formal PROSITE signature consensus pattern [FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - C - [LIVMFAP] - [GAD].[12] Because of the vast variety of reactions catalyzed by P450s, the activities and properties of the many P450s differ in many aspects. In general, the P450 catalytic cycle proceeds as follows:

Catalytic cycle

  1. Substrate binds in proximity to the heme group, on the side opposite to the axial thiolate. Substrate binding induces a change in the conformation of the active site, often displacing a water molecule from the distal axial coordination position of the heme iron,[13] and changing the state of the heme iron from low-spin to high-spin.[14]
  2. Substrate binding induces electron transfer from NAD(P)H via cytochrome P450 reductase or another associated reductase.[15]
  3. Molecular oxygen binds to the resulting ferrous heme center at the distal axial coordination position, initially giving a dioxygen adduct similar to oxy-myoglobin.
  4. A second electron is transferred, from either cytochrome P450 reductase, ferredoxins, or cytochrome b5, reducing the Fe-O2 adduct to give a short-lived peroxo state.
  5. The peroxo group formed in step 4 is rapidly protonated twice, releasing one molecule of water and forming the highly reactive species referred to as P450 Compound 1 (or just Compound I). This highly reactive intermediate was isolated in 2010,[16] P450 Compound 1 is an iron(IV) oxo (or ferryl) species with an additional oxidizing equivalent delocalized over the porphyrin and thiolate ligands. Evidence for the alternative perferryl iron(V)-oxo[13] is lacking.[16]
  6. Depending on the substrate and enzyme involved, P450 enzymes can catalyze any of a wide variety of reactions. A hypothetical hydroxylation is shown in this illustration. After the product has been released from the active site, the enzyme returns to its original state, with a water molecule returning to occupy the distal coordination position of the iron nucleus.
Oxygen rebound mechanism utilized by cytochrome P450 for conversion of hydrocarbons to alcohols via the action of "compound I", an iron(IV) oxide bound to a heme radical cation.
  1. An alternative route for mono-oxygenation is via the "peroxide shunt" (path "S" in figure). This pathway entails oxidation of the ferric-substrate complex with oxygen-atom donors such as peroxides and hypochlorites.[17] A hypothetical peroxide "XOOH" is shown in the diagram.

Spectroscopy

Binding of substrate is reflected in the spectral properties of the enzyme, with an increase in absorbance at 390 nm and a decrease at 420 nm. This can be measured by difference spectroscopies and is referred to as the "type I" difference spectrum (see inset graph in figure). Some substrates cause an opposite change in spectral properties, a "reverse type I" spectrum, by processes that are as yet unclear. Inhibitors and certain substrates that bind directly to the heme iron give rise to the type II difference spectrum, with a maximum at 430 nm and a minimum at 390 nm (see inset graph in figure). If no reducing equivalents are available, this complex may remain stable, allowing the degree of binding to be determined from absorbance measurements in vitro[17] C: If carbon monoxide (CO) binds to reduced P450, the catalytic cycle is interrupted. This reaction yields the classic CO difference spectrum with a maximum at 450 nm. However, the interruptive and inhibitory effects of CO varies upon different CYPs such that the CYP3A family is relatively less affected.[18]

P450s in humans

Human P450s are primarily membrane-associated proteins[19] located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. P450s metabolize thousands of endogenous and exogenous chemicals. Some P450s metabolize only one (or a very few) substrates, such as CYP19 (aromatase), while others may metabolize multiple substrates. Both of these characteristics account for their central importance in medicine. Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in hormone synthesis and breakdown (including estrogen and testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including drugs and products of endogenous metabolism such as bilirubin, principally in the liver.

The Human Genome Project has identified 57 human genes coding for the various cytochrome P450 enzymes.[20]

Drug metabolism

Proportion of antifungal drugs metabolized by different families of P450s.[21]

P450s are the major enzymes involved in drug metabolism, accounting for about 75% of the total metabolism.[22] Most drugs undergo deactivation by P450s, either directly or by facilitated excretion from the body. However, many substances are bioactivated by P450s to form their active compounds like the antiplatelet drug clopidogrel and the opiate codeine.

The CYP450 enzyme superfamily comprises 57 active subsets, with seven playing a crucial role in the metabolism of most pharmaceuticals.[23] The fluctuation in the amount of CYP450 enzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) in phase 1 (detoxification) can have varying effects on individuals, as genetic expression varies from person to person. This variation is due to the enzyme’s genetic polymorphism, which leads to variability in its function and expression. To optimize drug metabolism in individuals, genetic testing should be conducted to determine functional foods and specific phytonutrients that cater to the individual’s CYP450 polymorphism. Understanding these genetic variations can help personalize drug therapies for improved effectiveness and reduced adverse reactions.[24]

Drug interaction

Many drugs may increase or decrease the activity of various P450 isozymes either by inducing the biosynthesis of an isozyme (enzyme induction) or by directly inhibiting the activity of the P450 (enzyme inhibition). A classical example includes anti-epileptic drugs, such as phenytoin, which induces CYP1A2, CYP2C9, CYP2C19, and CYP3A4.

Effects on P450 isozyme activity are a major source of adverse drug interactions, since changes in P450 enzyme activity may affect the metabolism and clearance of various drugs. For example, if one drug inhibits the P450-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels. Hence, these drug interactions may necessitate dosage adjustments or choosing drugs that do not interact with the P450 system. Such drug interactions are especially important to consider when using drugs of vital importance to the patient, drugs with significant side-effects, or drugs with a narrow therapeutic index, but any drug may be subject to an altered plasma concentration due to altered drug metabolism.

Many substrates for CYP3A4 are drugs with a narrow therapeutic index, such as amiodarone[25] or carbamazepine.[26] Because these drugs are metabolized by CYP3A4, the mean plasma levels of these drugs may increase because of enzyme inhibition or decrease because of enzyme induction.

Interaction of other substances

Naturally occurring compounds may also induce or inhibit P450 activity. For example, bioactive compounds found in grapefruit juice and some other fruit juices, including bergamottin, dihydroxybergamottin, and paradicin-A, have been found to inhibit CYP3A4-mediated metabolism of certain medications, leading to increased bioavailability and, thus, the strong possibility of overdosing.[27] Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.[28]

Other examples:

Other specific P450 functions

Steroid hormones

Steroidogenesis, showing many of the enzyme activities that are performed by cytochrome P450 enzymes.[36] HSD: Hydroxysteroid dehydrogenase.

A subset of cytochrome P450 enzymes play important roles in the synthesis of steroid hormones (steroidogenesis) by the adrenals, gonads, and peripheral tissue:

Polyunsaturated fatty acids and eicosanoids

Certain cytochrome P450 enzymes are critical in metabolizing polyunsaturated fatty acids (PUFAs) to biologically active, intercellular cell signaling molecules (eicosanoids) and/or metabolize biologically active metabolites of the PUFA to less active or inactive products. These CYPs possess cytochrome P450 omega hydroxylase and/or epoxygenase enzyme activity.

CYP families in humans

Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies.[38] This is a summary of the genes and of the proteins they encode. See the homepage of the cytochrome P450 Nomenclature Committee for detailed information.[20]

Family Function Members Genes Pseudogenes
CYP1 drug and steroid (especially estrogen) metabolism, benzo[a]pyrene toxification (forming (+)-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide) 3 subfamilies, 3 genes, 1 pseudogene CYP1A1, CYP1A2, CYP1B1 CYP1D1P
CYP2 drug and steroid metabolism 13 subfamilies, 16 genes, 16 pseudogenes CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1 Too many to list
CYP3 drug and steroid (including testosterone) metabolism 1 subfamily, 4 genes, 4 pseudogenes CYP3A4, CYP3A5, CYP3A7, CYP3A43 CYP3A51P, CYP3A52P, CYP3A54P, CYP3A137P
CYP4 arachidonic acid or fatty acid metabolism 6 subfamilies, 12 genes, 10 pseudogenes CYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP4Z1 Too many to list
CYP5 thromboxane A2 synthase 1 subfamily, 1 gene CYP5A1
CYP7 bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus 2 subfamilies, 2 genes CYP7A1, CYP7B1
CYP8 varied 2 subfamilies, 2 genes CYP8A1 (prostacyclin synthase), CYP8B1 (bile acid biosynthesis)
CYP11 steroid biosynthesis 2 subfamilies, 3 genes CYP11A1, CYP11B1, CYP11B2
CYP17 steroid biosynthesis, 17-alpha hydroxylase 1 subfamily, 1 gene CYP17A1
CYP19 steroid biosynthesis: aromatase synthesizes estrogen 1 subfamily, 1 gene CYP19A1
CYP20 unknown function 1 subfamily, 1 gene CYP20A1
CYP21 steroid biosynthesis 1 subfamilies, 1 gene, 1 pseudogene CYP21A2 CYP21A1P
CYP24 vitamin D degradation 1 subfamily, 1 gene CYP24A1
CYP26 retinoic acid hydroxylase 3 subfamilies, 3 genes CYP26A1, CYP26B1, CYP26C1
CYP27 varied 3 subfamilies, 3 genes CYP27A1 (bile acid biosynthesis), CYP27B1 (vitamin D3 1-alpha hydroxylase, activates vitamin D3), CYP27C1 (vitamin A1 to A2)
CYP39 7-alpha hydroxylation of 24-hydroxycholesterol 1 subfamily, 1 gene CYP39A1
CYP46 cholesterol 24-hydroxylase 1 subfamily, 1 gene, 1 pseudogene CYP46A1 CYP46A4P
CYP51 cholesterol biosynthesis 1 subfamily, 1 gene, 3 pseudogenes CYP51A1 (lanosterol 14-alpha demethylase) CYP51P1, CYP51P2, CYP51P3

P450s in other species

Animals

Other animals often have more P450 genes than humans do. Reported numbers range from 35 genes in the sponge Amphimedon queenslandica to 235 genes in the cephalochordate Branchiostoma floridae.[39] Mice have genes for 101 P450s, and sea urchins have even more (perhaps as many as 120 genes).[40] Most CYP enzymes are presumed to have monooxygenase activity, as is the case for most mammalian CYPs that have been investigated (except for, e.g., CYP19 and CYP5). Gene and genome sequencing is far outpacing biochemical characterization of enzymatic function, though many genes with close homology to CYPs with known function have been found, giving clues to their functionality.

The classes of P450s most often investigated in non-human animals are those either involved in development (e.g., retinoic acid or hormone metabolism) or involved in the metabolism of toxic compounds (such as heterocyclic amines or polyaromatic hydrocarbons). Often there are differences in gene regulation or enzyme function of P450s in related animals that explain observed differences in susceptibility to toxic compounds (ex. canines' inability to metabolize xanthines such as caffeine). Some drugs undergo metabolism in both species via different enzymes, resulting in different metabolites, while other drugs are metabolized in one species but excreted unchanged in another species. For this reason, one species's reaction to a substance is not a reliable indication of the substance's effects in humans. A species of Sonoran Desert Drosophila that uses an upregulated expression of the CYP28A1 gene for detoxification of cacti rot is Drosophila mettleri. Flies of this species have adapted an upregulation of this gene due to exposure of high levels of alkaloids in host plants.

P450s have been extensively examined in mice, rats, dogs, and less so in zebrafish, in order to facilitate use of these model organisms in drug discovery and toxicology. Recently P450s have also been discovered in avian species, in particular turkeys, that may turn out to be a useful model for cancer research in humans.[41] CYP1A5 and CYP3A37 in turkeys were found to be very similar to the human CYP1A2 and CYP3A4 respectively, in terms of their kinetic properties as well as in the metabolism of aflatoxin B1.[42]

CYPs have also been extensively studied in insects, often to understand pesticide resistance. For example, CYP6G1 is linked to insecticide resistance in DDT-resistant Drosophila melanogaster[43] and CYP6M2 in the mosquito malaria vector Anopheles gambiae is capable of directly metabolizing pyrethroids.[44] Other cytochromes, such as those in Anopheles gambiae, are under preliminary research for their potential role in pesticide resistance, infectious diseases, and malaria.[45]

Microbial

Microbial cytochromes P450 are often soluble enzymes and are involved in diverse metabolic processes. In bacteria the distribution of P450s is very variable with many bacteria having no identified P450s (e.g. E.coli). Some bacteria, predominantly actinomycetes, have numerous P450s (e.g.,[46][47]). Those so far identified are generally involved in either biotransformation of xenobiotic compounds (e.g. CYP105A1 from Streptomyces griseolus metabolizes sulfonylurea herbicides to less toxic derivatives,[48]) or are part of specialised metabolite biosynthetic pathways (e.g. CYP170B1 catalyses production of the sesquiterpenoid albaflavenone in Streptomyces albus[49]). Although no P450 has yet been shown to be essential in a microbe, the CYP105 family is highly conserved with a representative in every streptomycete genome sequenced so far.[50] Due to the solubility of bacterial P450 enzymes, they are generally regarded as easier to work with than the predominantly membrane bound eukaryotic P450s. This, combined with the remarkable chemistry they catalyse, has led to many studies using the heterologously expressed proteins in vitro. Few studies have investigated what P450s do in vivo, what the natural substrate(s) are and how P450s contribute to survival of the bacteria in the natural environment.Three examples that have contributed significantly to structural and mechanistic studies are listed here, but many different families exist.

  • Cytochrome P450 cam (CYP101A1) originally from Pseudomonas putida has been used as a model for many cytochromes P450 and was the first cytochrome P450 three-dimensional protein structure solved by X-ray crystallography. This enzyme is part of a camphor-hydroxylating catalytic cycle consisting of two electron transfer steps from putidaredoxin, a 2Fe-2S cluster-containing protein cofactor.
  • Cytochrome P450 eryF (CYP107A1) originally from the actinomycete bacterium Saccharopolyspora erythraea is responsible for the biosynthesis of the antibiotic erythromycin by C6-hydroxylation of the macrolide 6-deoxyerythronolide B.
  • Cytochrome P450 BM3 (CYP102A1) from the soil bacterium Bacillus megaterium catalyzes the NADPH-dependent hydroxylation of several long-chain fatty acids at the ω–1 through ω–3 positions. Unlike almost every other known CYP (except CYP505A1, cytochrome P450 foxy), it constitutes a natural fusion protein between the CYP domain and an electron donating cofactor. Thus, BM3 is potentially very useful in biotechnological applications.[51][52]
  • Cytochrome P450 119 (CYP119A1) isolated from the thermophillic archea Sulfolobus solfataricus [53] has been used in a variety of mechanistic studies.[16] Because thermophillic enzymes evolved to function at high temperatures, they tend to function more slowly at room temperature (if at all) and are therefore excellent mechanistic models.

Fungi

The commonly used azole class of antifungal drugs works by inhibition of the fungal cytochrome P450 14α-demethylase.[54][better source needed]

Plants

Cytochromes P450 are involved in a variety of processes of plant growth, development, and defense. It is estimated that P450 genes make up approximately 1% of the plant genome.[55][56] These enzymes lead to various fatty acid conjugates, plant hormones, secondary metabolites, lignins, and a variety of defensive compounds.[57]

Cytochromes P450 play an important role in plant defense– involvement in phytoalexin biosynthesis, hormone metabolism, and biosynthesis of diverse secondary metabolites.[58] The expression of cytochrome p450 genes is regulated in response to environmental stresses indicative of a critical role in plant defense mechanisms.[59]

Phytoalexins have shown to be important in plant defense mechanisms as they are antimicrobial compounds produced by plants in response to plant pathogens. Phytoalexins are not pathogen-specific, but rather plant-specific; each plant has its own unique set of phytoalexins. However, they can still attack a wide range of different pathogens. Arabidopsis is a plant closely related to cabbage and mustard and produces the phytoalexin camalexin. Camalexin originates from tryptophan and its biosynthesis involves five cytochrome P450 enzymes. The five cytochrome P450 enzymes include CYP79B2, CYP79B3, CYP71A12, CYP71A13, and CYP71B15. The first step of camalexin biosynthesis produces indole-3-acetaldoxime (IAOx) from tryptophan and is catalyzed by either CYP79B2 or CYP79B3. IAOx is then immediately converted to indole-3-acetonitrile (IAN) and is controlled by either CYP71A13 or its homolog CYP71A12. The last two steps of the biosynthesis pathway of camalexin are catalyzed by CYP71B15. In these steps, indole-3-carboxylic acid (DHCA) is formed from cysteine-indole-3-acetonitrile (Cys(IAN)) followed by the biosynthesis of camalexin. There are some intermediate steps within the pathway that remain unclear, but it is well understood that cytochrome P450 is pivotal in camalexin biosynthesis and that this phytoalexin plays a major role in plant defense mechanisms.[60]

Cytochromes P450 are largely responsible for the synthesis of the jasmonic acid (JA), a common hormonal defenses against abiotic and biotic stresses for plant cells. For example, a P450, CYP74A is involved in the dehydration reaction to produce an insatiable allene oxide from hydroperoxide.[61] JA chemical reactions are critical in the presence of biotic stresses that can be caused by plant wounding, specifically shown in the plant, Arabidopsis. As a prohormone, jasmonic acid must be converted to the JA-isoleucine (JA-Ile) conjugate by JAR1 catalysation in order to be considered activated. Then, JA-Ile synthesis leads to the assembly of the co-receptor complex compo`sed of COI1 and several JAZ proteins. Under low JA-Ile conditions, the JAZ protein components act as transcriptional repressors to suppress downstream JA genes. However, under adequate JA-Ile conditions, the JAZ proteins are ubiquitinated and undergo degradation through the 26S proteasome, resulting in functional downstream effects. Furthermore, several CYP94s (CYP94C1 and CYP94B3) are related to JA-Ile turnover and show that JA-Ile oxidation status impacts plant signaling in a catabolic manner.[55] Cytochrome P450 hormonal regulation in response to extracellular and intracellular stresses is critical for proper plant defense response. This has been proven through thorough analysis of various CYP P450s in jasmonic acid and phytoalexin pathways.

Cytochrome P450 aromatic O-demethylase, which is made of two distinct promiscuous parts: a cytochrome P450 protein (GcoA) and three domain reductase, is significant for its ability to convert Lignin, the aromatic biopolymer common in plant cell walls, into renewable carbon chains in a catabolic set of reactions. In short, it is a facilitator of a critical step in Lignin conversion.

InterPro subfamilies

InterPro subfamilies:

Clozapine, imipramine, paracetamol, phenacetin Heterocyclic aryl amines Inducible and CYP1A2 5-10% deficient oxidize uroporphyrinogen to uroporphyrin (CYP1A2) in heme metabolism, but they may have additional undiscovered endogenous substrates. are inducible by some polycyclic hydrocarbons, some of which are found in cigarette smoke and charred food.

These enzymes are of interest, because in assays, they can activate compounds to carcinogens. High levels of CYP1A2 have been linked to an increased risk of colon cancer. Since the 1A2 enzyme can be induced by cigarette smoking, this links smoking with colon cancer.[62]

See also

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