HGNC Approved Gene Symbol: CYP2C9
SNOMEDCT: 726543008;
Cytogenetic location: 10q23.33 Genomic coordinates (GRCh38): 10:94,938,658-94,990,091 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.33 | Tolbutamide poor metabolizer | 3 | ||
| Warfarin sensitivity | 122700 | Autosomal dominant | 3 |
CYP2C9 is one of the major drug-metabolizing CYP450 isoforms. See 124020 for more information.
Crystal Structure
Williams et al. (2003) described the crystal structure of human CYP2C9, both unliganded and in complex with the anticoagulant drug warfarin (see 122700). The structure defines unanticipated interactions between CYP2C9 and warfarin, and reveals a new binding pocket. The binding mode of warfarin suggests that CYP2C9 may undergo an allosteric mechanism during its function. The newly discovered binding pocket also suggests that CYP2C9 may simultaneously accommodate multiple ligands during its biologic function, and provides a possible molecular basis for understanding complex drug-drug interactions.
In 16 patients with coronary artery disease and 5 healthy controls, Fichtlscherer et al. (2004) studied the effects of sulfaphenazole, a selective inhibitor of CYP2C9, on endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) forearm blood flow responses. In patients with coronary artery disease, sulfaphenazole markedly and dose-dependently enhanced the forearm blood flow response to acetylcholine but not to sodium nitroprusside; there was no effect on either in the healthy controls. Fichtlscherer et al. (2004) stated that the enhancement of endothelium-dependent vasodilator responses by the CYP2C9 inhibitor in patients with coronary artery disease seemed to be related to an increase in the bioavailability of NO, which they suggested was due to an attenuated generation of reactive oxygen species by CYP2C9 in endothelial cells.
CYP2C9 is 1 of several CYP2C genes clustered in a 500-kb region on proximal 10q24 (Gray et al., 1995). Kohn and Pelz (2000) studied the warfarin-resistance locus of the rat, Rw, and by homology of synteny concluded that the homolog is on mouse chromosome 7 and 1 of 3 human chromosomes, including 10q25.3-q26.
Using FISH, BAC end sequencing, and genomic database analysis, Gough et al. (2003) determined that the order of selected genes on chromosome 10q24, from centromere to telomere, is CYP2C9, PAX2 (167409), HOX11 (TLX1; 186770), and NFKB2 (164012).
CYP2C9 is one of the primary P450 isozyme responsible for hydroxylation of tolbutamide, an oral sulfonylurea hypoglycemic agent used in the treatment of type II diabetes mellitus (NIDDM; 125853). Population studies indicate the existence of rare (approximately 1 in 500) slow metabolizers of tolbutamide. Sullivan-Klose et al. (1996) sequenced the coding regions, intron-exon junctions, and upstream region of CYP2C9 in 2 slow metabolizers of tolbutamide. One individual was homozygous for ile359 to leu (601130.0001) and the other individual was heterozygous for arg144 to cys (601130.0002) and for ile359 to leu. No other genetic variations in CYP2C9 were detected in these individuals. PCR-RFLP tests showed that arg144/tyr358/ile359/gly417 is the principal CYP2C9 allele. Studies in a recombinant yeast expression system indicated that the leu359 allelic variant of CYP2C9 accounts for the occurrence of poor metabolizers of tolbutamide. The study also indicated that the leu359 allelic variant has a lower affinity and a lower intrinsic clearance for S-warfarin 7-hydroxylation than the wildtype ile359 variant.
Thum and Borlak (2000) investigated the gene expression of major human cytochrome P450 genes in various regions of explanted hearts from 6 patients with dilated cardiomyopathy and 1 with transposition of the arterial trunk and 2 samples of normal heart. mRNA for cytochrome 2C9 was predominantly expressed in the right ventricle. A strong correlation between tissue-specific gene expression and enzyme activity was found. Thum and Borlak (2000) concluded that expression of genes for cytochrome P450 monooxygenases and verapamil metabolism are found predominantly in the right side of the heart, and suggested that this observation may explain the lack of efficacy of certain cardioselective drugs.
Diclofenac is a nonsteroidal antiinflammatory drug that can cause rare but potentially serious hepatotoxicity. Aithal et al. (2000) found no evidence that polymorphism in CYP2C9 is a determinant of diclofenac-induced hepatotoxicity.
Wood (2001) discussed pointers to genetic differences underlying racial differences in the response to drugs. CYP2C9 is the cytochrome P450 enzyme responsible for the metabolism of the isomer of warfarin (see 122700) that is principally responsible for the anticoagulant effect of the drug. Two CYP2C9 alleles that produce a phenotype of poor metabolism occur in 11% and 8% of whites but only 3% and 0.8% of blacks (Xie et al., 2001). Such persons have impaired metabolism of warfarin and thus increased plasma concentrations of the drug. Persons with the genotype of impaired metabolism require lower doses of warfarin to achieve an anticoagulant effect similar to that in patients with the normal genotype (Aithal et al., 1999) and are more likely to have an excessive anticoagulant response. In addition, bleeding episodes tend to be more common in persons with the genotype of impaired metabolism.
Patients with the CYP2C9*2 allele, R144C (601130.0002), and the CYP2C9*3 allele, I359L (601130.0001), require lower maintenance doses of warfarin because of the reduced activity of these common variants. Higashi et al. (2002) studied the association of these variants with over-anticoagulation and bleeding events during warfarin therapy in a retrospective cohort study. The results suggested that the 2 polymorphisms are associated with an increased risk of overanticoagulation and of bleeding events among patients in a warfarin anticoagulation clinic setting, although small numbers in some cases would suggest the need for caution in interpretation.
Kirchheiner et al. (2003) studied the effects of CYP2C9 on celecoxib, a nonsteroidal antiinflammatory drug (NSAID) that is used to treat rheumatoid arthritis and osteoarthritis and exhibits antiinflammatory, analgesic, and antipyretic activity by selective inhibition of cyclooxygenase-2 (COX2; 600262). They found a more than 2-fold reduced oral clearance in homozygous carriers of CYP2C9*3; heterozygous carriers of 1 CYP2C9*3 allele were in between, whereas CYP2C9*2 had no significant influence on celecoxib pharmacokinetics. Kirchheiner et al. (2003) concluded that approximately 0.5% of Caucasians with a homozygous CYP2C9*3 genotype will have greatly increased internal exposure to celecoxib. It was not clear whether this is associated with greater efficacy or with an increased incidence and severity of adverse events.
Maekawa et al. (2006) sequenced the CYP2C9 gene in 263 Japanese individuals (134 diabetics and 129 healthy volunteers) and identified 62 variations, 32 of which were novel. Only 5 haplotypes accounted for more than 87% of the inferred haplotypes, and they were closely associated with the haplotypes of CYP2C19 in Japanese. The authors noted that although the haplotype structure of CYP2C9 was rather simple in Japanese, the haplotype distribution was quite different from those previously reported in Caucasians and Africans.
Sanderson et al. (2005) presented a metaanalysis of studies of the CYP2C9*2 (601130.0002) and CYP2C9*3 (601130.0001) alleles.
The International Warfarin Pharmacogenetics Consortium (2009) found that a pharmacogenetic dose algorithm for warfarin based on the genotype at VKORC1 (608547) and CYP2C9 accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and those who required 49 mg or more per week to achieve the targeted international normalized ratio than did a clinical algorithm alone (49.4% vs 33.3%, p less than 0.001, among patients requiring 21 mg or less per week; and 24.8% vs 7.2%, p less than 0.001, among those requiring 49 mg or more per week). The authors concluded that the use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.
Speed et al. (2009) found considerable geographic variation in frequencies of haplotypes spanning the CYP2C8 (601129) and CYP2C9 loci on chromosome 10q23-q24. More than 2,500 individuals from 45 populations worldwide were analyzed for 10 SNPs, including 8 in CYP2C8 and 2 in CYP2C9: 5 of the SNPs were changes in the coding region of the genes. The authors discussed the implications for the study of pharmacogenetics.
The ile359-to-leu (I359L) substitution results from a 1075A-C transversion in the CYP2C9 gene and is also known as rs1057910 and CYP2C9*3. The variant leads to reduced warfarin metabolism and increased risk of bleeding (Ross et al., 2010).
Extensive interindividual variation in the response to a given dose Sullivan-Klose et al. (1996) demonstrated that the form of CYP2C9 in which ile359 is replaced by leucine is the basis of poor metabolizing of tolbutamide, the sulfonylurea hypoglycemic agent used in the treatment of diabetes mellitus (NIDDM; 125853). The frequency of the leu359 allele was found to be 0.06 in the Caucasian-American population and 0.005 in African Americans. The frequency of the leu359 allele was 0.026 in Chinese-Taiwanese. They found that the leu359 allelic variant of CYP2C9 also has a lower affinity and a lower intrinsic clearance for S-warfarin 7-hydroxylation than the ile359 variant. Presumably, 7-hydroxylation has an important role in terminating the anticoagulant activity of warfarin in vitro, and individuals who are homozygous for the leu359 variant might require lower doses of this anticoagulant.
In a patient who was unusually sensitive to warfarin therapy (see 122700), Steward et al. (1997) identified homozygosity for I359L, the so-called CYP2C9*3 allele. The patient, who was taking 0.5 mg of warfarin daily, had an S-to-R enantiomer ratio of 3.9:1, whereas control patients taking 4 to 8 mg of warfarin daily had S-to-R ratios of about 0.5:1. Steward et al. (1997) concluded that expression of CYP2C9*3 is associated with diminished clearance of the more potent S-warfarin, and that analysis of the plasma S-to-R warfarin ratio might serve as a useful alternative test to genotyping.
Kidd et al. (1999) described a 29-year-old male Caucasian who had participated in 6 bioequivalence studies over a period of several years. The patient displayed severe hypoglycemia after a single dose of glipizide, a second generation sulfonylurea structurally similar to tolbutamide and used as an oral hypoglycemic agent. His oral clearance of phenytoin was 21% of the mean of 11 other individuals, and his oral clearance of glipizide was only 18% of the mean of 10 other individuals. His oral clearance of nifedipine (a CYP3A4 (124010) substrate) and chlorpheniramine (a CYP2D6 (see 124030) substrate) did not differ from that of other individuals studied. Genotype testing demonstrated that the individual was homozygous for the leu359 allele and did not possess any of the known defective CYP2C19 (124020) alleles. These studies established that the leu359 allele is responsible for the phenytoin and glipizide/tolbutamide poor metabolizer phenotype.
In a study of 281 epileptic patients treated with phenytoin, Tate et al. (2005) found a significant association between the maximum dose needed and the CYP2C9*3 allele (I359L). Mean phenytoin doses for individuals with 0, 1, or 2 copies of the *3 allele were 354, 309, and 250 mg, respectively, indicating a trend of reduction in maximum dose needed to control symptoms.
Ross et al. (2010) genotyped 963 individuals from 7 geographic regions for the CYP2C9*3 variant. The highest frequencies were observed in Europe (4 to 21%), the Middle East (3 to 11%) and Central/South Asia (5 to 15%). The allele was not observed in Africa or most populations from the Americas, except the Pima (7%). In Oceania, the allele was not present in Melanesians, but in Papua New Guinea the frequency was 12%. The allele was absent in many populations in East Asia, but reached frequencies of 10% or higher in some populations, such as the Tu, Tujia and Xibo. Similar frequencies were found in a Canadian cohort of 316 individuals of European, East Asian, and South Asian ancestry.
The arg144-to-cys (R144C) substitution results from a 430C-T transition in the CYP2C9 gene and is also known as rs1799853 and CYP2C9*2. The variant leads to reduced warfarin metabolism and increased risk of bleeding (Ross et al., 2010).
Extensive interindividual variation in the response to a given dose of warfarin (coumarin) makes the prediction of an accurate maintenance dose difficult, with an effective daily dose ranging from 0.5 to 60 mg. The asymmetric carbon of warfarin (C9) gives rise to 2 enantiomeric forms, R-warfarin and S-warfarin, which are differentially metabolized. When administered as a racemate, S-warfarin is about 3 times as potent as R-warfarin. CYP2C9 is the principal enzyme that catalyzes the conversion of S-warfarin to inactive 6-hydroxy and 7-hydroxy metabolites, whereas the oxidative metabolism of R-warfarin is mainly catalyzed by CYP1A2 (124060) and CYP3A4 (124010). In addition to the wildtype CYP2C9*1 allele, point mutations in the CYP2C9 gene result in 2 allelic variants: CYP2C9*2, where cysteine substitutes for arginine at amino acid 144, and CYP2C9*3, where leucine substitutes for isoleucine at residue 359 (601130.0001). Both allelic variants have impaired hydroxylation of S-warfarin when expressed in vitro; the CYP2C9*3 variant is less than 5% as efficient as the wildtype enzyme, while CYP2C9*2 shows about 12% of wildtype activity, apparently as a result of the amino acid substitution altering the interaction of the enzyme with cytochrome P450 oxidoreductase. Aithal et al. (1999) studied the frequency of the 2 variant alleles in individuals with a low warfarin dose requirement; see 122700. Patients in the low-dose group were more likely to have difficulties at the time of induction of warfarin therapy and had an increased risk of major bleeding complications.
King et al. (2004) concluded that the coding region nonsynonymous polymorphisms associated with the CYP2C9*2 and CYP2C9*3 (601130.0001) alleles are the major CYP2C9-related factors affecting warfarin dose in U.K. Caucasians. Upstream CYP2C9 polymorphisms did not appear to be important independent determinants of dose requirement.
In a metaanalysis of studies of the CYP2C9*2 and CYP2C9*3 (601130.0001) alleles, Sanderson et al. (2005) found that patients carrying these alleles had lower mean daily warfarin dosage and greater risk of bleeding. However, Li et al. (2006) could only partially confirm this. They found that polymorphisms in the VKORC1 gene (608547) were strongly associated with warfarin dosage requirement. They found no association with either of the 2 CYP2C9 polymorphisms studied, CYP2C9*2 and CYP2C9*3. CYP2C9*3 was significantly (p = 0.05) associated with average warfarin dosage after adjustment for the VKORC1*1173 polymorphism.
Ross et al. (2010) genotyped 963 individuals from 7 geographic regions for the CYP2C9*2 and CYP2C9*3 variants. The CYP2C9*2 allele was primarily restricted to European (2 to 29%), Middle Eastern (11 to 20%) and Central/South Asia populations (2 to 16%), and was mostly absent in other population groups, such as Africa and the Middle East. Exceptions included the North Eastern Bantu from Africa (4%), the Yakut from East Asia (2%) and the Maya (2%). Similar frequencies were found in a Canadian cohort of 316 individuals of European, East Asian, and South Asian ancestry.
The arg144-to-cys polymorphism of CYP2C9 (601130.0002), associated with warfarin sensitivity in Caucasian subjects, is very rare in Chinese. Leung et al. (2001) studied CYP2C9 polymorphisms in 89 Chinese patients receiving warfarin. They found genetic polymorphisms in exon 4 and at codon 208; most were heterozygous leu208-to-val and homozygous val208. Homozygous leu208, a common allele in Caucasians, was uncommon in this cohort. Subjects heterozygous for leu208 to val or homozygous for val208 appeared to have a lower warfarin dose requirement than those carrying homozygous leu208. The authors stated that 'at codon 208, polymorphic alleles existed at high frequency and appeared to have lower warfarin dose requirements.'
Aithal, G. P., Day, C. P., Kesteven, P. J. L., Daly, A. K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353: 717-719, 1999. [PubMed: 10073515] [Full Text: https://doi.org/10.1016/S0140-6736(98)04474-2]
Aithal, G. P., Day, C. P., Leathart, J. B. S., Daly, A. K. Relationship of polymorphism in CYP2C9 to genetic susceptibility to diclofenac-induced hepatitis. Pharmacogenetics 10: 511-518, 2000. [PubMed: 10975605] [Full Text: https://doi.org/10.1097/00008571-200008000-00004]
Fichtlscherer, S., Dimmeler, S., Breuer, S., Busse, R., Zeiher, A. M., Fleming, I. Inhibition of cytochrome P450 2C9 improves endothelium-dependent, nitric oxide-mediated vasodilatation in patients with coronary artery disease. Circulation 109: 178-183, 2004. [PubMed: 14662709] [Full Text: https://doi.org/10.1161/01.CIR.0000105763.51286.7F]
Gough, S. M., McDonald, M., Chen, X.-N., Korenberg, J. R., Neri, A., Kahn, T., Eccles, M. R., Morris, C. M. Refined physical map of the human PAX2/HOX11/NFKB2 cancer gene region at 10q24 and relocalization of the HPV6AI1 viral integration site to 14q13.3-q21.1. BMC Genomics 4: 9, 2003. Note: Electronic Article. [PubMed: 12697057] [Full Text: https://doi.org/10.1186/1471-2164-4-9]
Gray, I. C., Nobile, C., Muresu, R., Ford, S., Spurr, N. K. A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24. Genomics 28: 328-332, 1995. [PubMed: 8530044] [Full Text: https://doi.org/10.1006/geno.1995.1149]
Higashi, M. K., Veenstra, D. L., Kondo, L. M., Wittkowsky, A. K., Srinouanprachanh, S. L., Farin, F. M., Rettie, A. E. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287: 1690-1698, 2002. [PubMed: 11926893] [Full Text: https://doi.org/10.1001/jama.287.13.1690]
International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. New Eng. J. Med. 360: 753-764, 2009. Note: Erratum: New Eng. J. Med. 361: 1613 only, 2009. [PubMed: 19228618] [Full Text: https://doi.org/10.1056/NEJMoa0809329]
Kidd, R. S., Straughn, A. B., Meyer, M. C., Blaisdell, J., Goldstein, J. A., Dalton, J. T. Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics 9: 71-80, 1999. [PubMed: 10208645] [Full Text: https://doi.org/10.1097/00008571-199902000-00010]
King, B. P., Khan, T. I., Aithal, G. P., Kamali, F., Daly, A. K. Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism. Pharmacogenetics 14: 813-822, 2004. [PubMed: 15608560] [Full Text: https://doi.org/10.1097/00008571-200412000-00004]
Kirchheiner, J., Stormer, E., Meisel, C., Steinbach, N., Roots, I., Brockmoller, J. Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics 13: 473-480, 2003. [PubMed: 12893985] [Full Text: https://doi.org/10.1097/00008571-200308000-00005]
Kohn, M. H., Pelz, H.-J. A gene-anchored map position of the rat warfarin-resistance locus, Rw, and its orthologs in mice and humans. Blood 96: 1996-1998, 2000. [PubMed: 10961907]
Leung, A. Y. H., Chow, H. C. H., Kwong, Y. L., Lie, A. K. W., Fung, A. T. K., Chow, W. H., Yip, A. S. B., Liang, R. Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients. Blood 98: 2584-2587, 2001. [PubMed: 11588061] [Full Text: https://doi.org/10.1182/blood.v98.8.2584]
Li, T., Lange, L. A., Li, X., Susswein, L., Bryant, B., Malone, R., Lange, E. M., Huang, T.-Y., Stafford, D. W., Evans, J. P. Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation. J. Med. Genet. 43: 740-744, 2006. [PubMed: 16611750] [Full Text: https://doi.org/10.1136/jmg.2005.040410]
Maekawa, K., Fukushima-Uesaka, H., Tohkin, M., Hasegawa, R., Kajio, H., Kuzuya, N., Yasuda, K., Kawamoto, M., Kamatani, N., Suzuki, K., Yanagawa, T., Saito, Y., Sawada, J. Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese. Pharmacogenet. Genomics 16: 497-514, 2006. [PubMed: 16788382] [Full Text: https://doi.org/10.1097/01.fpc.0000215069.14095.c6]
Ross, K. A., Bigham, A. W., Edwards, M., Gozdzik, A., Suarez-Kurtz, G., Parra, E. J. Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements. J. Hum. Genet. 55: 582-589, 2010. [PubMed: 20555338] [Full Text: https://doi.org/10.1038/jhg.2010.73]
Sanderson, S., Emery, J., Higgins, J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet. Med. 7: 97-104, 2005. [PubMed: 15714076] [Full Text: https://doi.org/10.1097/01.gim.0000153664.65759.cf]
Speed, W. C., Kang, S. P., Tuck, D. P., Harris, L. N., Kidd, K. K. Global variation in CYP2C8-CYP2C9 functional haplotypes. Pharmacogenomics J. 9: 283-290, 2009. [PubMed: 19381162] [Full Text: https://doi.org/10.1038/tpj.2009.10]
Steward, D. J., Haining, R. L., Henne, K. R., Davis, G., Rushmore, T. H., Trager, w. F., Rettie, A. E. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 7: 361-367, 1997. [PubMed: 9352571] [Full Text: https://doi.org/10.1097/00008571-199710000-00004]
Sullivan-Klose, T. H., Ghanayem, B. I., Bell, D. A., Zhang, Z.-Y., Kaminsky, L. S., Shenfield, G. M., Miners, J. O., Birkett, D. J., Goldstein, J. A. The role of the CYP2C9-leu-359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 6: 341-349, 1996. [PubMed: 8873220] [Full Text: https://doi.org/10.1097/00008571-199608000-00007]
Tate, S. K., Depondt, C., Sisodiya, S. M., Cavalleri, G. L., Schorge, S., Soranzo, N., Thom, M., Sen, A., Shorvon, S. D., Sander, J. W., Wood, N. W., Goldstein, D. B. Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc. Nat. Acad. Sci. 102: 5507-5512, 2005. [PubMed: 15805193] [Full Text: https://doi.org/10.1073/pnas.0407346102]
Thum, T., Borlak, J. Gene expression in distinct regions of the heart. Lancet 355: 979-983, 2000. [PubMed: 10768437] [Full Text: https://doi.org/10.1016/S0140-6736(00)99016-0]
Williams, P. A., Cosme, J., Ward, A., Angove, H. C., Vinkovic, D. M., Jhoti, H. Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature 424: 464-468, 2003. [PubMed: 12861225] [Full Text: https://doi.org/10.1038/nature01862]
Wood, A. J. J. Racial differences in the response to drugs--pointers to genetic differences. (Letter) New Eng. J. Med. 344: 1393-1396, 2001. [PubMed: 11336055] [Full Text: https://doi.org/10.1056/NEJM200105033441811]
Xie, H.-G., Kim, R. B., Wood, A. J. J., Stein, C. M. Molecular basis of ethnic differences in drug disposition and response. Ann. Rev. Pharm. Toxicol. 41: 815-850, 2001. [PubMed: 11264478] [Full Text: https://doi.org/10.1146/annurev.pharmtox.41.1.815]