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Cytochrome P450 Oxidase (CYP2C9)

Cytochrome P450 (abbreviated CYP, P450, infrequently CYP450) is a diverse superfamily of hemoproteins found in bacteria, archaea and eukaryotes.[1] Cytochromes P450 are involved in metabolism of a plethora of both exogenous and endogenous compounds. Usually they form part of multicomponent electron transfer chains, called P450-containing systems. The most common reaction catalysed by cytochrome P450 is a monooxygenase reaction, i.e. insertion of one atom of oxygen into an organic substrate (RH) while the other oxygen atom is reduced to water:

RH + O2 + 2H+ + 2e → ROH + H2O

CYP homologs have been sequenced from all lineages of life, including mammals, birds, fish, insects, worms, sea squirts, sea urchins, plants, fungi, slime molds, bacteria and archaea. More than 6400 distinct CYP sequences are known (as of October 2006; see the web site of the P450 Nomenclature Committee for current counts).[2]

  • The name P450 refers to the "pigment at 450 nm", so named for the characteristic Soret peak formed by absorbance of light at wavelengths near 450 nm when the heme iron is reduced (with sodium dithionite) and complexed to carbon monoxide.


Genes encoding for the CYP enzymes, and the enzymes themselves, are designated with the abbreviation "CYP", followed by an Arabic numeral indicating the gene family, a capital letter indicating the subfamily, and another numerals for the individual gene. The convention is to italicise when referring to the gene. For example, CYP2E1 is the gene that encodes for the enzyme CYP2E1 – one of the enzymes involved in paracetamol (acetaminophen) metabolism.

The current nomenclature guidelines suggest that members of new CYP families share >40% amino acid identity, while members of subfamiles must share >55% amino acid identity. There is a Nomenclature Committee that keeps track of and assigns new names.


Main article: P450-containing systems

The active site of cytochromes P450 contain a heme iron center. The iron is tethered to the protein via a thiolate ligand derived from a cysteine residue. This cysteine and several flanking residues (RXCXG) are absolutely conserved over all known CYPs[3]. Because of the vast variety of reactions catalyzed by CYPs, a generalized description of the enzyme mechanism by necessity will not detail many of the known aspects of different CYPs. However, in general:

1. The resting state of the protein is as oxidized Fe3+.
2. Binding of a substrate initiates electron transport and oxygen binding.
3. Electrons are supplied to the CYP by another protein, either cytochrome P450 reductase, ferredoxins, or cytochrome b5 to reduce the heme iron.
4. Molecular oxygen is bound and split by the now reduced iron.
5. An iron-bound oxidant, in some cases an iron(IV) oxo[How to reference and link to summary or text], oxidizes the substrate to an alcohol or an epoxide, regenerating the resting state of the CYP.

Because most CYPs require a protein partner to deliver one or more electrons to reduce the iron (and eventually molecular oxygen), CYPs are properly speaking part of P450-containing systems of proteins. Five general schemes are known :

  • CPR/cyb5/P450 systems employed by most eukaryotic microsomal (ie not mitochondrial) CYPs involve the reduction of cytochrome P450 reductase (variously CPR,POR, or CYPOR) by NADPH, and the transfer of reducing power to the CYP. Cytochrome b5 (cyb5) can also contribute reducing power to this system after being reduced by cytochrome b5 reductase (CYB5R).
  • FR/Fd/P450 systems which are employed by mitochondrial and some bacterial CYPs.
  • CYB5R/cyb5/P450 systems in which both electrons required by the CYP come from cytochrome b5.
  • FMN/Fd/P450 systems originally found in Rhodococcus sp. in which a FMN-domain-containing reductase is fused to the CYP.
  • P450 only systems, which do not require external reducing power. Notably these include CYP5 (thromboxane synthase), CYP8, prostacyclin synthase, and CYP74A (allene oxide synthase).

P450s in animals

Animal CYPs are primarily membrane-associated proteins, located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. CYPs metabolise thousands of endogenous and exogenous compounds. Most CYPs can metabolize multiple substrates, and many can catalyze multiple reactions, which accounts for their central importance in metabolizing the potentially endless variety of endogenous and exogenous molecules. In the liver, these substrates include drugs and toxic compounds as well as metabolic products such as bilirubin (a breakdown product of hemoglobin). Cytochromes P450 are present in many other tissues of the body including the mucosa of the gastrointestinal tract, and play important roles in hormone synthesis and breakdown (including estrogen and testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D metabolism. In most animals, including humans, hepatic cytochromes P450 are the most widely studied of the P450 enzymes.

The Human Genome Project has identified more than 63 human genes (57 full genes and 5 pseudogenes) coding for the various cytochrome P450 enzymes.[4]

Drug metabolism

In drug metabolism, cytochrome P450 is probably the most important element of oxidative metabolism (a part of Phase I metabolism) in animals (metabolism in this context being the chemical modification or degradation of chemicals including drugs and endogenous compounds). Many drugs may increase or decrease the activity of various CYP isozymes in a phenomenon known as enzyme induction and inhibition. This is a major source of adverse drug interactions, since changes in CYP enzyme activity may affect the metabolism and 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, possibly causing an overdose. Hence, these drug interactions may necessitate dosage adjustments or choosing drugs which do not interact with the CYP system. In addition, naturally occurring compounds may also cause a similar effect. For example, bioactive compounds found in grapefruit juice and some other fruit juices, including bergamottin, dihydroxybergamottin, and paradisin-A, have been found to inhibit CYP3A4-mediated metabolism of certain medications, leading to increased bioavailability and thus the strong possibility of overdosing.[5] Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.

Other specific CYP functions in animals

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

  • CYP11A1 (also known as P450scc or P450c11a1) in adrenal mitochondria effects “the activity formerly known as 20,22-desmolase” (steroid 20α-hydroxylase, steroid 22-hydroxylase, cholesterol 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.
  • 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.
  • CYP21A1 (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.

CYP Families in humans

Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies.[6] This is a summary of the genes. See the homepage of the Cytochrome P450 Nomenclature Committee for the most detailed information.[4]

Family Function Members Names
CYP1 drug and steroid (especially estrogen) metabolism 3 subfamilies, 3 genes, 1 pseudogene CYP1A1, CYP1A2, CYP1B1
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
CYP3 drug and steroid (including testosterone) metabolism 1 subfamily, 4 genes, 2 pseudogenes CYP3A4, CYP3A5, CYP3A7, CYP3A43
CYP4 arachidonic acid or fatty acid metabolism 6 subfamilies, 11 genes, 10 pseudogenes CYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP4Z1
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 2 subfamilies, 2 genes, 1 pseudogene CYP21A2
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 (unknown function)
CYP39 7-alpha hydroxylation of 24-hydroxycholesterol 1 subfamily, 1 gene CYP39A1
CYP46 cholesterol 24-hydroxylase 1 subfamily, 1 gene CYP46A1
CYP51 cholesterol biosynthesis 1 subfamily, 1 gene, 3 pseudogenes CYP51A1 (lanosterol 14-alpha demethylase)


  1. International Union of Pure and Applied Chemistry. "cytochrome P450". Compendium of Chemical Terminology Internet edition. Danielson P (2002). The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab 3 (6): 561-97.
  3. DR Nelson
  4. 4.0 4.1
  5. Bailey DG, Dresser GK (2004). Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drug 4 (5): 281-297.
  6. Nelson D (2003). Cytochrome P450s in humans. Retrieved May 9, 2005.

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