Annotated PGx Gene Information for CYP2C9
Submitted by: Derek Van Booven (CREATE), Michelle Whirl Carrillo (PharmGKB)
Reviewed by: Reviewed
Submitted date: January 16th, 2007
| Gene HGNC Name: | CYP2C9 |
|---|---|
| Gene Common Name: | CYP2C9 |
| Introductory Information: | CYP2C9 is a major phase 1 drug-metabolizing CYP450 isoform and one of several CYP2C genes clustered in a 500kb region on proximal 10q24 [8530044]. CYP2C9 is primarily expressed in the liver. CYP2C9 is the enzyme responsible for the metabolism of the S-isomer of warfarin (R-warfarin is mainly metabolized by other CYP450 enzymes) that is principally responsible for the anticoagulant effect of the drug. CYP2C9 also metabolizes most NSAIDs [16118328], COX-2 inhibitors [12534640], tolbutamide [15637526], phenytoin [15900281], glipizide [15637526], fluvastatin [15637526] and many other drug groups. It is induced by rifampin and inhibited by amiodarone, among others [15900281, 9663807]. Two non-synonymous variants within CYP2C9 produce a phenotype of poor metabolism (*2 and *3). Persons with the genotype of poor metabolism require lower doses of warfarin to achieve an anticoagulant effect similar to that in patients with a *1 (wildtype) genotype [10073515 14691573]. However, it is known that CYP2C9 genotype can account for only part of the variability in warfarin sensitivity [11893129, 12621390] and that VKORC1 genotype, age and weight are key factors [16424822]. CYP2C9 is responsible for about 90% of phenytoin metabolism, which is a drug prescribed for the treatment of epilepsy. Again, *2 and *3 alleles decrease the metabolism of phenytoin [16873909, 11434505]. It is also the primary enzyme responsible for tolbutamide hydroxylation [9663807]. CYP2C9 has also been described in the cyclophosphamide drug pathway as one of the putative p450 isoenzymes that activates cyclophosphamide to 4-hydroxycyclophosphamide [12684728]. There have been multiple polymorphisms detected in the 5' region of CYP2C9 but these have not yet been shown to contribute to response to warfarin [15900281, 16513444] or phenytoin [11434505], beyond those which appear to be in linkage disequilibrium with known exonic variants [15900281]. Several other exonic alleles besides *2 and *3 are known, but appear to be much less common [15637526]. |
| Key PubMed IDs: | 11926893, 10073515, 8530044, 12684728, 16118328, 12893985, 15637526, 9663807, 17113714 |
| Key Pathways: | Cyclophosphamide, Warfarin, Nicotine, Ifosfamide |
| Drugs/Substrates: | NSAIDs (16118328), COX-2 inhibitors (12893985), tolbutamide (15637526), glipizide (15637526), fluvastatin (15637526), warfarin (8004131), phenytoin (11434505) |
| Phenotypes/Diseases: | N/A |
| Important Variants: | CYP2C9 144Arg>Cys CYP2C9 359Ile>Leu |
| Important Haplotypes: | CYP2C9*2 CYP2C9*3 |