CYP2C9

Cytochrome P450, family 2, subfamily C, polypeptide 9
Ribbon diagram of CYP2C9, heme group visible at center. From PDB: 1OG2​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1OG2, 1OG5, 1R9O, 4NZ2
Identifiers
Symbols	CYP2C9 ; CPC9; CYP2C; CYP2C10; CYPIIC9; P450IIC9
External IDs	OMIM: 601130 MGI: 103238 HomoloGene: 133566 ChEMBL: 3397 GeneCards: CYP2C9 Gene
EC number	1.14.13.48, 1.14.13.49, 1.14.13.80
Gene ontology Molecular function • monooxygenase activity • iron ion binding • drug binding • arachidonic acid epoxygenase activity • steroid hydroxylase activity • oxidoreductase activity • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen • (S)-limonene 6-monooxygenase activity • (S)-limonene 7-monooxygenase activity • oxygen binding • heme binding • caffeine oxidase activity • (R)-limonene 6-monooxygenase activity Cellular component • cytoplasm • endoplasmic reticulum membrane • intracellular membrane-bounded organelle Biological process • xenobiotic metabolic process • steroid metabolic process • monoterpenoid metabolic process • drug metabolic process • arachidonic acid metabolic process • epoxygenase P450 pathway • urea metabolic process • monocarboxylic acid metabolic process • drug catabolic process • exogenous drug catabolic process • cellular amide metabolic process • small molecule metabolic process • oxidation-reduction process • oxidative demethylation • omega-hydroxylase P450 pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1559	69888
Ensembl	ENSG00000138109	ENSMUSG00000067229
UniProt	P11712	Q9D816
RefSeq (mRNA)	NM_000771	NM_001011707
RefSeq (protein)	NP_000762	NP_001011707
Location (UCSC)	Chr 10: 94.94 – 94.99 Mb	Chr 19: 39.11 – 39.19 Mb
PubMed search	[1]	[2]

Cytochrome P450 2C9 (abbreviated CYP2C9) is an enzyme that in humans is encoded by the CYP2C9 gene.

Function

CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes (data only for antifungal). Some 100 therapeutic drugs are metabolized ㅡby CYP2C9, including drugs with a narrow therapeutic index such as warfarin and phenytoin and other routinely prescribed drugs such as acenocoumarol, tolbutamide, losartan, glipizide, and some nonsteroidal anti-inflammatory drugs. By contrast, the known extrahepatic CYP2C9 often metabolizes important endogenous compound such as arachidonic acid, 5-hydroxytryptamine, and linoleic acid.

With respect to arachidonic acid, linoleic acid, and other polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid, CYP2C9 exhibits epoxygenase activity, i.e. it metabolizes these long-chain polyunsaturated fatty acids to their biologically active epoxides. For example, it is one of the principle cytochrome P450 enzymes that metabolizes arachidonic acid to the following eicosatrienoic acid epoxides: 5,6-epoxy-8Z,11Z,14Z-eicosatetrienoic acid, 5,6-epoxy-8Z,11Z,14Z-eicosatetrienoic acid, 11,12-epoxy-5Z,8Z,14Z-eicosatetrienoic acid, and 14,15-epoxy-5Z,8Z,11Z-eicosatetrainoic acid; animal models and a limited set of human studies implicate these epoxides in reducing hypertension; protecting against the Myocardial infarction and other insults to the heart; promoting the growth and metastasis of certain cancers; inhibiting inflammation; stimulating blood vessel formation; and possessing a variety of actions on neural tissues including modulating Neurohormone release and blocking pain perception (see epoxyeicosatrienoic acid and epoxygenase pages}.

Pharmacogenomics

Genetic polymorphism exists for CYP2C9 expression because the CYP2C9 gene is highly polymorphic. More than 50 single nucleotide polymorphisms (SNPs) have been described in the regulatory and coding regions of the CYP2C9 gene, some of them are associated with reduced enzyme activity compared with wild type in vitro.

Multiple in vivo studies also show that several mutant CYP2C9 genotypes are associated with significant reduction of in metabolism and daily dose requirements of selected CYP2C9 substrate. In fact, adverse drug reactions (ADRs) often result from unanticipated changes in CYP2C9 enzyme activity secondary to genetic polymorphisms. Especially for CYP2C9 substrates such as warfarin and phenytoin, diminished metabolic capacity because of genetic polymorphisms or drug-drug interactions can lead to toxicity at normal therapeutic doses.

Allele frequencies(%) of CYP2C9 polymorphism

	African-American	Black-African	Pygmy	Asian	Caucasian
CYP2C9*2	2.9	0-4.3	0	0-0.1	8-19
CYP2C9*3	2.0	0-2.3	0	1.1-3.6	3.3-16.2
CYP2C9*5	0-1.7	0.8-1.8	ND	0	0
CYP2C9*6	0.6	2.7	ND	0	0
CYP2C9*7	0	0	6	0	0
CYP2C9*8	1.9	8.6	4	0	0
CYP2C9*9	13	15.7	22	0	0.3
CYP2C9*11	1.4-1.8	2.7	6	0	0.4-1.0
CYP2C9*13	ND	ND	ND	0.19-0.45	ND

CYP2C9 Ligands

Most inhibitors of CYP2C9 are competitive inhibitors. Noncompetitive inhibitors of CYP2C9 include nifedipine, phenethyl isothiocyanate, medroxyprogesterone acetate and 6-hydroxyflavone. It was indicated that the noncompetitive binding site of 6-hydroxyflavone is the reported allosteric binding site of the CYP2C9 enzyme.

Following is a table of selected substrates, inducers and inhibitors of CYP2C9. Where classes of agents are listed, there may be exceptions within the class.

Inhibitors of CYP2C9 can be classified by their potency, such as:

• Strong being one that causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease in clearance.
• Moderate being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.
• Weak being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20-50% decrease in clearance.

Selected inducers, inhibitors and substrates of CYP2C9

Substrates	Inhibitors	Inducers
NSAIDs (analgesic, antipyretic, anti-inflammatory) celecoxib lornoxicam diclofenac ibuprofen naproxen ketoprofen piroxicam meloxicam suprofen phenytoin (antiepileptic) fluvastatin (statin) sulfonylureas (antidiabetic) glipizide glibenclamide glimepiride tolbutamide glyburide angiotensin II receptor antagonists (in hypertension, diabetic nephropathy, CHF) irbesartan losartan S-warfarin (anticoagulant) sildenafil (in erectile dysfunction) terbinafine (antifungal) amitriptyline (tricyclic antidepressant) fluoxetine (SSRI antidepressant) nateglinide (antidiabetic) rosiglitazone (antidiabetic) tamoxifen (SERM) torasemide (loop diuretic) ketamine THC JWH-018 AM-2201 limonene (monoterpene) tapentadol (analgesic) polyunsaturated fatty acids	Strong: fluconazole (antifungal) miconazole (antifungal) amentoflavone (constituent of Ginkgo biloba and St. John’s Wort sulfaphenazole (antibacterial) Valproic acid (anticonvulsant, mood-stabilizing) Apigenin Moderate amiodarone (antiarrhythmic) Unspecified potency antihistamines (H1-receptor antagonists) Cyclizine Promethazine Chloramphenicol fenofibrate (fibrate) flavones flavonols fluvastatin (statin) fluvoxamine (SSRI) isoniazid (in tuberculosis) lovastatin (statin) modafinil phenylbutazone (NSAID) probenecid (uricosuric) sertraline (SSRI) sulfamethoxazole (antibiotic) teniposide (chemotherapeutic) voriconazole (antifungal) zafirlukast (leukotriene antagonist) quercetin (anti-inflammatory)	Strong: rifampicin (bactericidal) secobarbital (barbiturate)

See also

• Cytochrome P450 oxidase

External links

• PharmGKB: Annotated PGx Gene Information for CYP2C9
• SuperCYP: Database for Drug-Cytochrome-Interactions