The gene encodes a member of the cytochrome P450 superfamily of enzymes. These proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is known to metabolize many drugs. Polymorphism within this gene is associated with variable ability to metabolize mephenytoin, known as the poor metabolizer and extensive metabolizer phenotypes. The gene is located within a cluster of cytochrome P450 genes on chromosome no.10 arm q24.
CYP2C19 also possesses epoxygenase activitiy: it is one of the principal enzymes responsible for attacking various long-chain polyunsaturated fatty acids at their double (i.e. alkene) bonds to form epoxide products that act as signaling agents. It metabolizes:
Genetic polymorphism (mainly CYP2C19*2, CYP2C19*3 and CYP2C19*17) exists for CYP2C19 expression, with approximately 3–5% of Caucasian and 15–20% of Asian populations being poor metabolizers with no CYP2C19 function. This may reduce the efficacy of clopidogrel (Plavix). In patients with an abnormal CYP2C19 variant certain benzodiazepines should be avoided, such as diazepam (Valium), lorazepam (Ativan), oxazepam (Serax), and temazepam (Restoril). On the basis of their ability to metabolize (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolizers (EM) or poor metabolizers (PM). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified.
^Romkes M, Faletto MB, Blaisdell JA, Raucy JL, Goldstein JA (April 1991). "Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily". Biochemistry. 30 (13): 3247–55. doi:10.1021/bi00227a012. PMID2009263.
^Gray IC, Nobile C, Muresu R, Ford S, Spurr NK (July 1995). "A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24". Genomics. 28 (2): 328–32. doi:10.1006/geno.1995.1149. PMID8530044.
^Fleming I (October 2014). "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews. 66 (4): 1106–40. doi:10.1124/pr.113.007781. PMID25244930.
^Bertilsson L (September 1995). "Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19". Clinical Pharmacokinetics. 29 (3): 192–209. doi:10.2165/00003088-199529030-00005. PMID8521680.
^Zhu AZ, Zhou Q, Cox LS, Ahluwalia JS, Benowitz NL, Tyndale RF (November 2014). "Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion-assisted smoking cessation outcomes". Drug Metabolism and Disposition. 42 (11): 1971–7. doi:10.1124/dmd.114.060285. PMID25187485.
^Miyazawa M, Shindo M, Shimada T (May 2002). "Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes". Drug Metabolism and Disposition. 30 (5): 602–7. doi:10.1124/dmd.30.5.602. PMID11950794.
^Wen X, Wang JS, Neuvonen PJ, Backman JT (January 2002). "Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes". European Journal of Clinical Pharmacology. 57 (11): 799–804. PMID11868802.
^Chen XP, Tan ZR, Huang SL, Huang Z, Ou-Yang DS, Zhou HH (March 2003). "Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects". Clinical Pharmacology and Therapeutics. 73 (3): 264–71. doi:10.1067/mcp.2003.14. PMID12621391.
Smith G, Stubbins MJ, Harries LW, Wolf CR (December 1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica. 28 (12): 1129–65. doi:10.1080/004982598238868. PMID9890157.
Ding X, Kaminsky LS (2003). "Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts". Annual Review of Pharmacology and Toxicology. 43: 149–73. doi:10.1146/annurev.pharmtox.43.100901.140251. PMID12171978.
Meier UT, Meyer UA (December 1987). "Genetic polymorphism of human cytochrome P-450 (S)-mephenytoin 4-hydroxylase. Studies with human autoantibodies suggest a functionally altered cytochrome P-450 isozyme as cause of the genetic deficiency". Biochemistry. 26 (25): 8466–74. doi:10.1021/bi00399a065. PMID3442670.
De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA (October 1994). "Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese". Molecular Pharmacology. 46 (4): 594–8. PMID7969038.
Romkes M, Faletto MB, Blaisdell JA, Raucy JL, Goldstein JA (February 1993). "Cloning and expression of complementary DNAs for multiple members of the human cytochrome PH50IIC subfamily". Biochemistry. 32 (5): 1390. doi:10.1021/bi00056a025. PMID8095407.
Goldstein JA, Faletto MB, Romkes-Sparks M, Sullivan T, Kitareewan S, Raucy JL, Lasker JM, Ghanayem BI (February 1994). "Evidence that CYP2C19 is the major (S)-mephenytoin 4'-hydroxylase in humans". Biochemistry. 33 (7): 1743–52. doi:10.1021/bi00173a017. PMID8110777.
de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA (June 1994). "The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans". The Journal of Biological Chemistry. 269 (22): 15419–22. PMID8195181.
Karam WG, Goldstein JA, Lasker JM, Ghanayem BI (October 1996). "Human CYP2C19 is a major omeprazole 5-hydroxylase, as demonstrated with recombinant cytochrome P450 enzymes". Drug Metabolism and Disposition. 24 (10): 1081–7. PMID8894508.
Xiao ZS, Goldstein JA, Xie HG, Blaisdell J, Wang W, Jiang CH, Yan FX, He N, Huang SL, Xu ZH, Zhou HH (April 1997). "Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele". The Journal of Pharmacology and Experimental Therapeutics. 281 (1): 604–9. PMID9103550.
Guengerich FP, Johnson WW (December 1997). "Kinetics of ferric cytochrome P450 reduction by NADPH-cytochrome P450 reductase: rapid reduction in the absence of substrate and variations among cytochrome P450 systems". Biochemistry. 36 (48): 14741–50. doi:10.1021/bi9719399. PMID9398194.
Ferguson RJ, De Morais SM, Benhamou S, Bouchardy C, Blaisdell J, Ibeanu G, Wilkinson GR, Sarich TC, Wright JM, Dayer P, Goldstein JA (January 1998). "A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin". The Journal of Pharmacology and Experimental Therapeutics. 284 (1): 356–61. PMID9435198.
Ibeanu GC, Goldstein JA, Meyer U, Benhamou S, Bouchardy C, Dayer P, Ghanayem BI, Blaisdell J (September 1998). "Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin". The Journal of Pharmacology and Experimental Therapeutics. 286 (3): 1490–5. PMID9732415.
Ibeanu GC, Blaisdell J, Ferguson RJ, Ghanayem BI, Brosen K, Benhamou S, Bouchardy C, Wilkinson GR, Dayer P, Goldstein JA (August 1999). "A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin". The Journal of Pharmacology and Experimental Therapeutics. 290 (2): 635–40. PMID10411572.