CYP2C9

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Overview

Cytochrome P450 2C9 (abbreviated CYP2C9) is a protein which in humans is encoded by the CYP2C9 gene.[1][2]

Function

CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes. Some 100 therapeutic drugs are metabolized by CYP2C9, including drugs with a narrow therapeutic index such as warfarin and phenytoin and other routinely prescribed drugs such as acenocoumarol, tolbutamide, losartan, glipizide, and some nonsteroidal anti-inflammatory drugs. By contrast, the known extrahepatic CYP2C9 often metabolizes important endogenous compound such as arachidonic acid , 5-hydroxytryptamine and linoleic acid.[3]

Pharmacogenomics

Genetic polymorphism exists for CYP2C9 expression because the CYP2C9 gene is highly polymorphic. More than 50 single nucleotide polymorphisms (SNPs) have been described in the regulatory and coding regions of the CYP2C9 gene,[4] some of them are associated with reduced enzyme activity compared with wild type in vitro.

Multiple in vivo studies also show that several mutant CYP2C9 genotypes are associated with significant reduction of in metabolism and daily dose requirements of selected CYP2C9 substrate. In fact, adverse drug reactions (ADRs) often result from unanticipated changes in CYP2C9 enzyme activity secondary to genetic polymorphisms. Especially for CYP2C9 substrates such as warfarin and phenytoin, diminished metabolic capacity because of genetic polymorphisms or drug-drug interactions can lead to toxicity at normal therapeutic doses.[5][6]

Allele frequencies(%) of CYP2C9 polymorphism

African-American Black-African Pygmy Asian Caucasian
CYP2C9*2 2.9 0-4.3 0 0-0.1 8-19
CYP2C9*3 2.0 0-2.3 0 1.1-3.6 3.3-16.2
CYP2C9*5 0-1.7 0.8-1.8 ND 0 0
CYP2C9*6 0.6 2.7 ND 0 0
CYP2C9*7 0 0 6 0 0
CYP2C9*8 1.9 8.6 4 0 0
CYP2C9*9 13 15.7 22 0 0.3
CYP2C9*11 1.4-1.8 2.7 6 0 0.4-1.0
CYP2C9*13[7] ND ND ND 0.6-1.0 ND

CYP2C9 Ligands

Most inhibitors of CYP2C9 are competitive inhibitors. Noncompetitive inhibitors of CYP2C9 include nifedipine,[8] tranylcypromine,[9] phenethyl isothiocyanate,[10] medroxyprogesterone acetate[11] and 6-hydroxyflavone. It was indicate that the noncompetitive binding site of 6-hydroxyflavone is the reported allosteric binding site of the CYP2C9 enzyme.[12]

Selected inducers, inhibitors and substrates of CYP2C9[13]
Substrates Inhibitors Inducers
Often mentioned:[14]

Other:

Strong:[16]


others:

Often mentioned:[14]

Other:

See also

References

  1. ↑ Romkes M, Faletto MB, Blaisdell JA, Raucy JL, Goldstein JA (1991). "Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily". Biochemistry. 30 (13): 3247–55. PMID 2009263. Unknown parameter |month= ignored (help)
  2. ↑ Inoue K, Inazawa J, Suzuki Y, Shimada T, Yamazaki H, Guengerich FP, Abe T (1994). "Fluorescence in situ hybridization analysis of chromosomal localization of three human cytochrome P450 2C genes (CYP2C8, 2C9, and 2C10) at 10q24.1". Jpn. J. Hum. Genet. 39 (3): 337–43. PMID 7841444. Unknown parameter |month= ignored (help)
  3. ↑ Rettie AE, Jones JP (2005). "Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics". Annu. Rev. Pharmacol. Toxicol. 45: 477–94. doi:10.1146/annurev.pharmtox.45.120403.095821. PMID 15822186.
  4. ↑ Sim SC. "Allele nomenclature for Cytochrome P450 enzymes". Human Cytochrome P450 (CYP) Allele Nomenclature Committee. Retrieved 2008-12-14.
  5. ↑ García-Martín E, Martínez C, Ladero JM, Agúndez JA (2006). "Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals". Mol Diagn Ther. 10 (1): 29–40. PMID 16646575.
  6. ↑ Rosemary J, Adithan C (2007). "The pharmacogenetics of CYP2C9 and CYP2C19: ethnic variation and clinical significance". Curr Clin Pharmacol. 2 (1): 93–109. PMID 18690857. Unknown parameter |month= ignored (help)
  7. ↑ Si D, Guo Y, Zhang Y, Yang L, Zhou H, Zhong D (2004). "Identification of a novel variant CYP2C9 allele in Chinese" (PDF). Pharmacogenetics. 14 (7): 465–9. PMID 15226678. Unknown parameter |month= ignored (help)
  8. ↑ Bourrié M, Meunier V, Berger Y, Fabre G (1999). "Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes". Drug Metab. Dispos. 27 (2): 288–96. PMID 9929518. Unknown parameter |month= ignored (help)
  9. ↑ Salsali M, Holt A, Baker GB (2004). "Inhibitory effects of the monoamine oxidase inhibitor tranylcypromine on the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP2D6". Cell. Mol. Neurobiol. 24 (1): 63–76. doi:10.1023/B:CEMN.0000012725.31108.4a. PMID 15049511. Unknown parameter |month= ignored (help)
  10. ↑ Nakajima M, Yoshida R, Shimada N, Yamazaki H, Yokoi T (2001). "Inhibition and inactivation of human cytochrome P450 isoforms by phenethyl isothiocyanate". Drug Metab. Dispos. 29 (8): 1110–3. PMID 11454729. Unknown parameter |month= ignored (help)
  11. ↑ Zhang JW, Liu Y, Li W, Hao DC, Yang L (2006). "Inhibitory effect of medroxyprogesterone acetate on human liver cytochrome P450 enzymes". Eur. J. Clin. Pharmacol. 62 (7): 497–502. doi:10.1007/s00228-006-0128-9. PMID 16645869. Unknown parameter |month= ignored (help)
  12. ↑ 12.0 12.1 12.2 Si D, Wang Y, Guo Y, Wang J, Zhou H, Zhou Y-H, Li Z-S, Fawcett JP (2008). "Mechanism of CYP2C9 inhibition by flavones and flavonols" (PDF). Drug Metabolism and Disposition. doi:10.1124/dmd.108.023416.
  13. ↑ Where classes of agents are listed, there may be exceptions within the class
  14. ↑ 14.0 14.1 Mentioned both in the reference named FASS and were previously mentioned in Wikipedia. Further contributions may follow other systems
  15. ↑ Guo Y, Zhang Y, Wang Y, Chen X, Si D, Zhong D, Fawcett JP, Zhou H (2005). "Role of CYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in humans" (PDF). Drug Metab. Dispos. 33 (6): 749–53. doi:10.1124/dmd.105.003616. PMID 15764711. Unknown parameter |month= ignored (help)
  16. ↑ "Facts for prescribers (Fakta för förskrivare)". Swedish environmental classification of pharmaceuticals. Retrieved 2008-12-14.

Further reading

  • Goldstein JA, de Morais SM (1995). "Biochemistry and molecular biology of the human CYP2C subfamily". Pharmacogenetics. 4 (6): 285–99. PMID 7704034.
  • Miners JO, Birkett DJ (1998). "Cytochrome P4502C9: an enzyme of major importance in human drug metabolism". British journal of clinical pharmacology. 45 (6): 525–38. PMID 9663807.
  • Smith G, Stubbins MJ, Harries LW, Wolf CR (1999). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica. 28 (12): 1129–65. PMID 9890157.
  • Henderson RF (2001). "Species differences in the metabolism of olefins: implications for risk assessment". Chem. Biol. Interact. 135-136: 53–64. PMID 11397381.
  • Xie HG, Prasad HC, Kim RB, Stein CM (2003). "CYP2C9 allelic variants: ethnic distribution and functional significance". Adv. Drug Deliv. Rev. 54 (10): 1257–70. PMID 12406644.
  • Palkimas MP, Skinner HM, Gandhi PJ, Gardner AJ (2004). "Polymorphism induced sensitivity to warfarin: a review of the literature". J. Thromb. Thrombolysis. 15 (3): 205–12. doi:10.1023/B:THRO.0000011376.12309.af. PMID 14739630.
  • Daly AK, Aithal GP (2004). "Genetic regulation of warfarin metabolism and response". Seminars in vascular medicine. 3 (3): 231–8. doi:10.1055/s-2003-44458. PMID 15199455.
  • García-Martín E, Martínez C, Ladero JM, Agúndez JA (2007). "Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals". Molecular diagnosis & therapy. 10 (1): 29–40. PMID 16646575.


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