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Gene Review

CYP2C9  -  cytochrome P450, family 2, subfamily C,...

Homo sapiens

Synonyms: (R)-limonene 6-monooxygenase, (S)-limonene 6-monooxygenase, (S)-limonene 7-monooxygenase, CPC9, CYP2C, ...
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Disease relevance of CYP2C9

  • Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin [1].
  • For women, carrying at least one variant CYP2C9 allele was inversely associated with the risk of colorectal cancer (OR=0.85, 95% CI, 0.57--1.27) when compared with *1/*1 wild-type individuals [2].
  • The constructs, CYP2C9/BMR, CYP2C19/BMR and CYP3A4/BMR are well expressed in Escherichia coli as holo proteins [3].
  • CYP2C9 mRNA was reduced in patients with both cholestatic and hepatocellular types of liver disease, but 2C protein was reduced only in patients with cholestatic dysfunction [4].
  • Presented here are the results on the construction and characterization of three fusion proteins containing the N-terminally modified human cytochrome P450s CYP2C9, CY2C19 and CYP3A4 fused to the soluble NADPH-dependent oxidoreductase domain of CYP102A1 from Bacillus megaterium [3].
  • Drugs that are metabolized by CYP2C9 increase the risk of myocardial infarction in women [5].

Psychiatry related information on CYP2C9


High impact information on CYP2C9

  • Drugs for which there is a potential case for prospective testing include warfarin (CYP2C9), perhexiline (CYP2D6), and perhaps the proton pump inhibitors (CYP2C19) [8].
  • CYP2C9 is also the first human P450 to be crystallized, and the structural basis for its substrate and inhibitor selectivity is becoming increasingly clear [9].
  • Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics [9].
  • RESULTS: Among 185 patients with analyzable data, 58 (31.4%) had at least 1 variant CYP2C9 allele and 127 (68.6%) had the wild-type (*1/*1) genotype [10].
  • The principal enzyme involved in warfarin metabolism is CYP2C9, and 2 relatively common variant forms with reduced activity have been identified, CYP2C9*2 and CYP2C9*3 [10].

Chemical compound and disease context of CYP2C9


Biological context of CYP2C9


Anatomical context of CYP2C9


Associations of CYP2C9 with chemical compounds

  • Intriguingly, removal of the negative charge from either 216 or 301 produced enzymes (E216A, E216K, and D301Q) with elevated levels (50-75-fold) of catalytic activity toward diclofenac, a carboxylate-containing CYP2C9 substrate that lacks a basic nitrogen atom [25].
  • In previous work, we have shown that CYP2C9 is inducible in primary human hepatocytes by xenobiotics including dexamethasone, rifampicin, and phenobarbital [16].
  • Identification of these functional elements provides rational mechanistic basis for CYP2C9 induction by dexamethasone (submicromolar concentrations), and by phenobarbital and rifampicin, respectively [16].
  • Data suggest that warfarin can be used as a safe and accurate biomarker for CYP2C9, and if warfarin is administered with vitamin K, the pharmacodynamic effect is ablated [26].
  • The specific CYP2C9 inhibitor sulfaphenazole, on the other hand, significantly attenuated EDHF-mediated hyperpolarization and relaxation [27].

Physical interactions of CYP2C9

  • Antiserum derived from the CYP2C19-immunized rabbits was reacted with CYP2C9 as well as CYP2C19 and immunoabsorbed with membrane-bound CYP2C9 expressed in E. coli [28].
  • These studies strongly support the hypothesis that there is cross talk between distal CAR/PXR sites and HNF4alpha binding sites in the CYP2C9 promoter and that the HNF4alpha sites are required for maximal induction of the CYP2C9 promoter [29].

Regulatory relationships of CYP2C9

  • On the other hand, cisapride strongly inhibited CYP3A4 and markedly inhibited CYP2C9 [30].
  • Sulfaphenazole, flavoxamine, and antibodies raised against purified liver cytochrome P450 (P450) 2C9 that inhibit both CYP2C9- and 2C19-dependent activities, significantly inhibited microsomal oxidations of (+)- and (-)-limonene enantiomers [31].
  • Overexpression of CYP2C9 and stimulation with 11,12-EET increased intracellular cAMP levels and stimulated DNA-binding of the cAMP-response element-binding protein [32].
  • Both CAR and PXR transcriptionally up-regulate the CYP2C9 promoter via these elements [29].

Other interactions of CYP2C9


Analytical, diagnostic and therapeutic context of CYP2C9

  • Rapid amplification of cDNA ends (RACE) and PCR amplifications of human liver cDNA revealed the presence of several intergenic species containing the CYP2C18 exon 1-like sequence spliced to different combinations of exonic and intronic sequences from the CYP2C9 gene [36].
  • Chromatin immunoprecipitation assay demonstrated in vivo binding of HNF4alpha and PGC1alpha to HNF4alpha response sequences in the CYP2C9 promoter and to three new regulatory regions in the common 23.3 kilobase spacer sequence of the CYP1A1/2 cluster [37].
  • Immunoblotting analysis of human liver microsomes suggested that CYP2C9 is a major component of the human CYP2C enzyme pool; it accounted for approximately 20% of total P450 in liver microsomes of both human populations [38].
  • Gel shift analysis demonstrated that nuclear proteins from HepG2 cells had a high binding affinity for a 20-bp oligonucleotide containing the HPF-1 site of CYP2C9 [23].
  • Multiple sequence alignment of CYPs identified CYP2C9 Asp(293) as corresponding to Asp(301) of CYP2D6, which has been suggested to play a role in the binding of basic substrates to the latter enzyme [39].


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  5. The risk of myocardial infarction in patients with reduced activity of cytochrome P450 2C9. Visser, L.E., van Schaik, R.H., Jan Danser, A.H., Hofman, A., Witteman, J.C., van Duijn, C.M., Uitterlinden, A.G., Pols, H.A., Stricker, B.H. Pharmacogenet. Genomics (2007) [Pubmed]
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  10. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. Higashi, M.K., Veenstra, D.L., Kondo, L.M., Wittkowsky, A.K., Srinouanprachanh, S.L., Farin, F.M., Rettie, A.E. JAMA (2002) [Pubmed]
  11. Down-regulation of astroglial CYP2C, glucocorticoid receptor and constitutive androstane receptor genes in response to cocaine in human U373 MG astrocytoma cells. Malaplate-Armand, C., Ferrari, L., Masson, C., Visvikis-Siest, S., Lambert, H., Batt, A.M. Toxicol. Lett. (2005) [Pubmed]
  12. The CYP2C9 genotype predicts the blood pressure response to irbesartan: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial. Hallberg, P., Karlsson, J., Kurland, L., Lind, L., Kahan, T., Malmqvist, K., Ohman, K.P., Nyström, F., Melhus, H. J. Hypertens. (2002) [Pubmed]
  13. CYP3A4, CYP2C9 and CYP2B6 expression and ifosfamide turnover in breast cancer tissue microsomes. Schmidt, R., Baumann, F., Knüpfer, H., Brauckhoff, M., Horn, L.C., Schönfelder, M., Köhler, U., Preiss, R. Br. J. Cancer (2004) [Pubmed]
  14. Polymorphisms in genes encoding acetylsalicylic acid metabolizing enzymes are unrelated to upper gastrointestinal health in cardiovascular patients on acetylsalicylic acid. van Oijen, M.G., Huybers, S., Peters, W.H., Drenth, J.P., Laheij, R.J., Verheugt, F.W., Jansen, J.B. British journal of clinical pharmacology. (2005) [Pubmed]
  15. Disposition of drugs in cystic fibrosis. V. In vivo CYP2C9 activity as probed by (S)-warfarin is not enhanced in cystic fibrosis. O'Sullivan, T.A., Wang, J.P., Unadkat, J.D., al-Habet, S.M., Trager, W.F., Smith, A.L., McNamara, S., Aitken, M.L. Clin. Pharmacol. Ther. (1993) [Pubmed]
  16. Transcriptional regulation of CYP2C9 gene. Role of glucocorticoid receptor and constitutive androstane receptor. Gerbal-Chaloin, S., Daujat, M., Pascussi, J.M., Pichard-Garcia, L., Vilarem, M.J., Maurel, P. J. Biol. Chem. (2002) [Pubmed]
  17. RNA molecules containing exons originating from different members of the cytochrome P450 2C gene subfamily (CYP2C) in human epidermis and liver. Zaphiropoulos, P.G. Nucleic Acids Res. (1999) [Pubmed]
  18. Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (-)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers. Kirchheiner, J., Kudlicz, D., Meisel, C., Bauer, S., Meineke, I., Roots, I., Brockmöller, J. Clin. Pharmacol. Ther. (2003) [Pubmed]
  19. Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site. Ferguson, S.S., LeCluyse, E.L., Negishi, M., Goldstein, J.A. Mol. Pharmacol. (2002) [Pubmed]
  20. Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Chang, T.K., Yu, L., Maurel, P., Waxman, D.J. Cancer Res. (1997) [Pubmed]
  21. Colchicine down-regulates cytochrome P450 2B6, 2C8, 2C9, and 3A4 in human hepatocytes by affecting their glucocorticoid receptor-mediated regulation. Dvorak, Z., Modriansky, M., Pichard-Garcia, L., Balaguer, P., Vilarem, M.J., Ulrichová, J., Maurel, P., Pascussi, J.M. Mol. Pharmacol. (2003) [Pubmed]
  22. Developmental expression of CYP2C and CYP2C-dependent activities in the human liver: in-vivo/in-vitro correlation and inducibility. Treluyer, J.M., Gueret, G., Cheron, G., Sonnier, M., Cresteil, T. Pharmacogenetics (1997) [Pubmed]
  23. Transcriptional regulation of human CYP2C genes: functional comparison of CYP2C9 and CYP2C18 promoter regions. Ibeanu, G.C., Goldstein, J.A. Biochemistry (1995) [Pubmed]
  24. The role of CYP2C in the in vitro bioactivation of the contraceptive steroid desogestrel. Gentile, D.M., Verhoeven, C.H., Shimada, T., Back, D.J. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  25. Residues glutamate 216 and aspartate 301 are key determinants of substrate specificity and product regioselectivity in cytochrome P450 2D6. Paine, M.J., McLaughlin, L.A., Flanagan, J.U., Kemp, C.A., Sutcliffe, M.J., Roberts, G.C., Wolf, C.R. J. Biol. Chem. (2003) [Pubmed]
  26. Combined phenotypic assessment of cytochrome p450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the "Cooperstown 5+1 cocktail". Chainuvati, S., Nafziger, A.N., Leeder, J.S., Gaedigk, A., Kearns, G.L., Sellers, E., Zhang, Y., Kashuba, A.D., Rowland, E., Bertino, J.S. Clin. Pharmacol. Ther. (2003) [Pubmed]
  27. Nifedipine increases cytochrome P4502C expression and endothelium-derived hyperpolarizing factor-mediated responses in coronary arteries. Fisslthaler, B., Hinsch, N., Chataigneau, T., Popp, R., Kiss, L., Busse, R., Fleming, I. Hypertension (2000) [Pubmed]
  28. Production of inhibitory polyclonal antibodies against cytochrome P450s. Ng, P.S., Imaoka, S., Hiroi, T., Osada, M., Niwa, T., Kamataki, T., Funae, Y. Drug Metab. Pharmacokinet. (2003) [Pubmed]
  29. The nuclear receptors constitutive androstane receptor and pregnane X receptor cross-talk with hepatic nuclear factor 4alpha to synergistically activate the human CYP2C9 promoter. Chen, Y., Kissling, G., Negishi, M., Goldstein, J.A. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  30. Drug-drug interactions of Z-338, a novel gastroprokinetic agent, with terfenadine, comparison with cisapride, and involvement of UGT1A9 and 1A8 in the human metabolism of Z-338. Furuta, S., Kamada, E., Omata, T., Sugimoto, T., Kawabata, Y., Yonezawa, K., Wu, X.C., Kurimoto, T. Eur. J. Pharmacol. (2004) [Pubmed]
  31. Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes. Miyazawa, M., Shindo, M., Shimada, T. Drug Metab. Dispos. (2002) [Pubmed]
  32. Cytochrome P4502C9-derived epoxyeicosatrienoic acids induce the expression of cyclooxygenase-2 in endothelial cells. Michaelis, U.R., Falck, J.R., Schmidt, R., Busse, R., Fleming, I. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  33. Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Chang, T.K., Weber, G.F., Crespi, C.L., Waxman, D.J. Cancer Res. (1993) [Pubmed]
  34. Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes. Drocourt, L., Ourlin, J.C., Pascussi, J.M., Maurel, P., Vilarem, M.J. J. Biol. Chem. (2002) [Pubmed]
  35. Formation of 20-hydroxyeicosatetraenoic acid, a vasoactive and natriuretic eicosanoid, in human kidney. Role of Cyp4F2 and Cyp4A11. Lasker, J.M., Chen, W.B., Wolf, I., Bloswick, B.P., Wilson, P.D., Powell, P.K. J. Biol. Chem. (2000) [Pubmed]
  36. Intergenic transcripts containing a novel human cytochrome P450 2C exon 1 spliced to sequences from the CYP2C9 gene. Warner, S.C., Finta, C., Zaphiropoulos, P.G. Mol. Biol. Evol. (2001) [Pubmed]
  37. Transcriptional Activation of CYP2C9, CYP1A1, and CYP1A2 by Hepatocyte Nuclear Factor 4{alpha} Requires Coactivators Peroxisomal Proliferator Activated Receptor-{gamma} Coactivator 1{alpha} and Steroid Receptor Coactivator 1. Mart??nez-Jim??nez, C.P., Castell, J.V., G??mez-Lech??n, M.J., Jover, R. Mol. Pharmacol. (2006) [Pubmed]
  38. Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl hydroxylation and S-mephenytoin 4'-hydroxylation activities in livers of Japanese and Caucasian populations. Inoue, K., Yamazaki, H., Imiya, K., Akasaka, S., Guengerich, F.P., Shimada, T. Pharmacogenetics (1997) [Pubmed]
  39. Role of conserved Asp293 of cytochrome P450 2C9 in substrate recognition and catalytic activity. Flanagan, J.U., McLaughlin, L.A., Paine, M.J., Sutcliffe, M.J., Roberts, G.C., Wolf, C.R. Biochem. J. (2003) [Pubmed]
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