Cytochrome P450: Difference between revisions

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{{Short description|Class of enzymes}}

'''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. 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. 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 [[kingdom (biology)|kingdom]]s of life: [[animal]]s, [[plant]]s, [[fungus|fungi]], [[protist]]s, [[bacteria]], and [[archaea]], as well as in [[virus]]es. However, they are not omnipresent; for example, they have not been found in ''[[Escherichia coli]]''. {{as of|2018}}, more than 300,000 distinct CYP proteins are known.

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]]).

[[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 '''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. P450_BM3 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 [[Thromboxane-A synthase|TBXAS1]] ('''T'''hrom'''B'''o'''X'''ane '''A'''₂ '''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).

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]).

{{Main|P450-containing systems}}

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

;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 b₅]] (cyb₅) can also contribute reducing power to this system after being reduced by [[cytochrome b5 reductase|cytochrome b₅ reductase]] (CYB₅R).

;Mitochondrial P450 systems: which employ [[adrenodoxin reductase]] and [[adrenodoxin]] to transfer electrons from NADPH to P450.

;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 [[redox|reduced]] to water:

{{center|1=

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

[[Image:P450cycle.svg|alt=The P450 catalytic cycle|thumb|400px|The "Fe(V) intermediate" at the bottom left is a simplification: it is an Fe(IV) with a [[noninnocent ligand|radical heme ligand]].]]

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]. 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:

# 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, and changing the state of the heme iron from low-spin to high-spin.

# Substrate binding induces electron transfer from NAD(P)H via [[cytochrome P450 reductase]] or another associated [[reductase]].

[[File:FeIVO 2.tif|thumb|left|[[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.|300px]]

# 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.  A hypothetical peroxide "XOOH" is shown in the diagram.

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''

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.

Human P450s are primarily membrane-associated proteins 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.

[[File:PropDrugsMetabCYP.png|thumb|400px|Proportion of antifungal drugs metabolized by different families of P450s.]]

{{Further|Drug metabolism}}

P450s are the major enzymes involved in [[drug metabolism]], accounting for about 75% of the total metabolism. 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. 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.

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 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]] or [[carbamazepine]]. 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.

'''Nutritional Modulation of CYP450 Enzymes: Balancing Induction and Inhibition'''

Cruciferous vegetables are induce CYP1A1 and aid in the upregulation of CYP1B1. These vegetables, along with berries, can also influence estrogen processing in the body. Berries are believed to reduce the activity of CYP1A1, while cruciferous vegetables may boost the activity of CYP1A enzymes over CYP1B1 enzymes.

[[Resveratrol]], [[ellagic]] acid [[quercetin]], found in many foods, affect CYP1A2 activity.

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]]. Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.

Other examples:

* [[Saint-John's wort]], a common [[herbal remedy]] [[Regulation of gene expression|induces]] [[CYP3A4]], but also inhibits [[CYP1A1]], [[CYP1B1]].

* [[Goldenseal]], with its two notable alkaloids [[berberine]] and [[hydrastine]], has been shown to alter P450-marker enzymatic activities (involving CYP2C9, CYP2D6, and CYP3A4).

[[File:Steroidogenesis.svg|thumb|400px|[[Steroidogenesis]], showing many of the enzyme activities that are performed by cytochrome P450 enzymes. 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:

* [[CYP19A]] (P450arom, [[aromatase]]) in [[endoplasmic reticulum]] of [[gonads]], [[brain]], [[adipose tissue]], and elsewhere catalyzes [[aromatization]] of [[androgens]] to [[estrogens]].

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).

* [[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.

Humans have 57 genes and more than 59 [[pseudogene]]s divided among 18 families of cytochrome P450 genes and 43 subfamilies. 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.

{| class="wikitable"

| '''Family''' || '''Function''' || '''Members''' || '''Genes''' || '''Pseudogenes'''

|}

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]]''. [[Mice]] have genes for 101 P450s, and [[sea urchin]]s have even more (perhaps as many as 120 genes).

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 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.

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. [[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.

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]]'' and [[CYP6M2]] in the mosquito [[malaria]] vector ''[[Anopheles gambiae]]'' is capable of directly metabolizing [[pyrethroids]].

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. 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) or are part of specialised metabolite biosynthetic pathways (e.g. [[CYP170B1]] catalyses production of the [[sesquiterpenoid]] albaflavenone in ''[[Streptomyces albus]]''). 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. 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 119 ([[CYP119A1]]) isolated from the [[thermophillic]] archea ''[[Sulfolobus solfataricus]]''  has been used in a variety of mechanistic studies. 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.

The commonly used [[Antifungal drug#Imidazole, triazole, 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.)

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.

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. These enzymes lead to various [[fatty acid]] conjugates, [[plant hormone]]s, [[secondary metabolite]]s, [[lignin]]s, and a variety of defensive compounds.

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

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.

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. 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. 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:

* Cytochrome P450, B-class {{InterPro|IPR002397}}

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.

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.

{{Portal|Biology}}

* [[Steroidogenic enzyme]]

* [[Cytochrome P450 engineering]]

{{Refbegin|32em}}

* {{cite journal | vauthors = Gelboin HV, Krausz K | title = Monoclonal antibodies and multifunctional cytochrome P450: drug metabolism as paradigm | journal = Journal of Clinical Pharmacology | volume = 46 | issue = 3 | pages = 353–372 | date = March 2006 | pmid = 16490812 | doi = 10.1177/0091270005285200 | s2cid = 33325397 }}

{{Refend}}

{{Commons category}}

* {{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 = 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}}

{{Hemeproteins}}

{{Cytochrome P450}}

{{Enzymes}}

{{二次利用|date=12 March 2024}}

[[Category:Cytochrome P450| ]]