CYP2C19

Cytochrome P450, family 2, subfamily C, polypeptide 19

PDB rendering based on 1r9o.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsCYP2C19 ; CPCJ; CYP2C; P450C2C; P450IIC19
External IDsOMIM: 124020 MGI: 1306818 HomoloGene: 133565 IUPHAR: 1328 ChEMBL: 3622 GeneCards: CYP2C19 Gene
EC number1.14.13.48, 1.14.13.49, 1.14.13.80
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez155769888
EnsemblENSG00000165841ENSMUSG00000067229
UniProtP33261n/a
RefSeq (mRNA)NM_000769NM_001011707
RefSeq (protein)NP_000760NP_001011707
Location (UCSC)Chr 10:
96.45 – 96.61 Mb		Chr 19:
39.11 – 39.19 Mb
PubMed search

Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme. This protein, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics, including many proton pump inhibitors and antiepileptics. In humans, the CYP2C19 protein is encoded by the CYP2C19 gene.[1][2] CYP2C19 is a liver enzyme that acts on 5-10% of drugs in current clinical use,[3] including the antiplatelet clopidogrel (Plavix), antiulcer drugs such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.[4]

CYP2C19 has been annotated as (R)-limonene 6-monooxygenase and (S)-limonene 6-monooxygenase in UniProt.

Function

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.[5]

Genetic polymorphism and pharmacogenomics

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.[6][7] 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).[8] 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).[7] Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified.[7]

Ligands

The following is a table of selected substrates, inducers and inhibitors of CYP2C19. Where classes of agents are listed, there may be exceptions within the class.

Inhibitors of CYP2C19 can be classified by their potency, such as:

Selected inducers, inhibitors and substrates of CYP2C19
Substrates Inhibitors Inducers
Strong:

Weak:


Unspecified potency:

See also

References

  1. ↑ 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. PMID 2009263.
  2. ↑ 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. PMID 8530044.
  3. ↑ "Cytochrome P450 2C19 Genotyping". Genele X. Retrieved October 2014.
  4. ↑ "Cytochrome P450 2C19 (CYP2C19) Genotype". Mayo Medical Laboratories. Retrieved October 2014.
  5. ↑ "Entrez Gene: CYP2C19 cytochrome P450, family 2, subfamily C, polypeptide 19".
  6. ↑ Bertilsson L (September 1995). "Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19". Clin Pharmacokinet 29 (3): 192–209. doi:10.2165/00003088-199529030-00005. PMID 8521680.
  7. ↑ 7.0 7.1 7.2 Desta, Z., et al. (2002). Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 41(12) 913-58. PMID 12222994
  8. ↑ Forest, M.D., P.H., Tennant. "American Association of Clinical Chemistry Annual Meeting 2014". AutoGenomics. Retrieved October 2014.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9 9.10 9.11 9.12 9.13 9.14 9.15 9.16 9.17 9.18 9.19 9.20 9.21 9.22 9.23 9.24 9.25 9.26 9.27 9.28 9.29 9.30 9.31 9.32 9.33 9.34 9.35 9.36 9.37 9.38 9.39 9.40 9.41 9.42 9.43 Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. Retrieved on July 2011
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11 10.12 10.13 10.14 10.15 10.16 10.17 10.18 10.19 FASS (drug formulary): Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare). Retrieved July 2011
  11. ↑ Zhu, A. Z. X.; Zhou, Q.; Cox, L. S.; Ahluwalia, J. S.; Benowitz, N. L.; Tyndale, R. F. (3 September 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): 1971–1977. doi:10.1124/dmd.114.060285. PMID 25187485.
  12. ↑ Zhang Y, Si D, Chen X, Lin N, Guo Y, Zhou H, Zhong D (July 2007). "Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects". Br J Clin Pharmacol 64 (1): 67–74. doi:10.1111/j.1365-2125.2007.02846.x. PMC 2000619. PMID 17298483.
  13. ↑ Xu H, Williams KM, Liauw WS, Murray M, Day RO, McLachlan AJ (April 2008). "Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide". Br. J. Pharmacol. 153 (7): 1579–86. doi:10.1038/sj.bjp.0707685. PMC 2437900. PMID 18204476.
  14. ↑ Park JY, Kim KA, Kim SL (November 2003). "Chloramphenicol Is a Potent Inhibitor of Cytochrome P450 Isoforms CYP2C19 and CYP3A4 in Human Liver Microsomes". Antimicrob. Agents Chemother. 47 (11): 3464–9. doi:10.1128/AAC.47.11.3464-3469.2003. PMC 253795. PMID 14576103.
  15. ↑ Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N (June 2014). "Fluoxetine- and Norfluoxetine-Mediated Complex Drug-Drug Interactions: In Vitro to In Vivo Correlation of Effects on CYP2D6, CYP2C19, and CYP3A4". Clinical Pharmacology & Therapeutics 95 (6): 653–62. doi:10.1038/clpt.2014.50.
  16. ↑ 16.0 16.1 Page 100 in: Rene H., PhD. Levy; Rene H. Levy; Levy, René H.; Mattson, Richard H; Meldrum, Brian S. (2002). Antiepileptic drugs. Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-2321-3.
  17. ↑ Wen X, Wang JS, Neuvonen PJ, Backman JT. "Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes.". PMID 11868802.
  18. ↑ Clin Pharmacol Ther. 2003 Mar;73(3):264-71. Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects. Chen XP1, Tan ZR, Huang SL, Huang Z, Ou-Yang DS, Zhou HH.

External links

Further reading

  • Goldstein JA, de Morais SM (1995). "Biochemistry and molecular biology of the human CYP2C subfamily". Pharmacogenetics 4 (6): 285–99. doi:10.1097/00008571-199412000-00001. PMID 7704034.
  • Smith G, Stubbins MJ, Harries LW, Wolf CR (1999). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica 28 (12): 1129–65. doi:10.1080/004982598238868. PMID 9890157.
  • Ding X, Kaminsky LS (2003). "Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts". Annu. Rev. Pharmacol. Toxicol. 43: 149–73. doi:10.1146/annurev.pharmtox.43.100901.140251. PMID 12171978.
  • Romkes M, Faletto MB, Blaisdell JA et al. (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. PMID 2009263.
  • Meier UT, Meyer UA (1988). "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. PMID 3442670.
  • De Morais SM, Wilkinson GR, Blaisdell J et al. (1994). "Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese". Mol. Pharmacol. 46 (4): 594–8. PMID 7969038.
  • Romkes M, Faletto MB, Blaisdell JA et al. (1993). "Cloning and expression of complementary DNAs for multiple members of the human cytochrome PH50IIC subfamily". Biochemistry 32 (5): 1390. doi:10.1021/bi00056a025. PMID 8095407.
  • Goldstein JA, Faletto MB, Romkes-Sparks M et al. (1994). "Evidence that CYP2C19 is the major (S)-mephenytoin 4'-hydroxylase in humans". Biochemistry 33 (7): 1743–52. doi:10.1021/bi00173a017. PMID 8110777.
  • de Morais SM, Wilkinson GR, Blaisdell J et al. (1994). "The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans". J. Biol. Chem. 269 (22): 15419–22. PMID 8195181.
  • Gray IC, Nobile C, Muresu R et al. (1996). "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. PMID 8530044.
  • Karam WG, Goldstein JA, Lasker JM, Ghanayem BI (1997). "Human CYP2C19 is a major omeprazole 5-hydroxylase, as demonstrated with recombinant cytochrome P450 enzymes". Drug Metab. Dispos. 24 (10): 1081–7. PMID 8894508.
  • Xiao ZS, Goldstein JA, Xie HG et al. (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". J. Pharmacol. Exp. Ther. 281 (1): 604–9. PMID 9103550.
  • Guengerich FP, Johnson WW (1998). "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. PMID 9398194.
  • Ferguson RJ, De Morais SM, Benhamou S et al. (1998). "A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin". J. Pharmacol. Exp. Ther. 284 (1): 356–61. PMID 9435198.
  • Ibeanu GC, Goldstein JA, Meyer U et al. (1998). "Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin". J. Pharmacol. Exp. Ther. 286 (3): 1490–5. PMID 9732415.
  • Ibeanu GC, Blaisdell J, Ghanayem BI et al. (1999). "An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians". Pharmacogenetics 8 (2): 129–35. doi:10.1097/00008571-199804000-00006. PMID 10022751.
  • Foster DJ, Somogyi AA, Bochner F (1999). "Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4". British Journal of Clinical Pharmacology 47 (4): 403–12. doi:10.1046/j.1365-2125.1999.00921.x. PMC 2014231. PMID 10233205.
  • Ibeanu GC, Blaisdell J, Ferguson RJ et al. (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". J. Pharmacol. Exp. Ther. 290 (2): 635–40. PMID 10411572.