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Cytochrome P450 2C9 (abbreviated 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
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Genetic polymorphism
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 ([3]), 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. Several reviews describing CYP2C9-mediated metabolism and clinical consequences have been published.
Allele frequencies(%) of CYP2C9 polymorphism
African-American Black-African Pygmy Asian Caucasian
CYP2C9*2 R144C 2.9 0-4.3 0 0-0.1 8-19
CYP2C9*3 I359L 2.0 0-2.3 0 1.1-3.6 3.3-16.2
CYP2C9*5 D360E 0-1.7 0.8-1.8 ND 0 0
CYP2C9*6 Null allele 0.6 2.7 ND 0 0
CYP2C9*7 L19I 0 0 6 0 0
CYP2C9*8 R150H 1.9 8.6 4 0 0
CYP2C9*9 H251R 13 15.7 22 0 0.3
CYP2C9*11 R335W 1.4-1.8 2.7 6 0 0.4-1.0
CYP2C9*13 L90P ND ND ND 0.6-1.0 ND
CYP2C9 Ligands
| Substrates | Inhibitors | Inducers |
|---|---|---|
Often mentioned [2]:
Other: |
Strong [3]:
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Often mentioned [2]:
Other:
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See also
References
- ^ Where classes of agents are listed, there may be exceptions within the class
- ^ a b Mentioned both in the reference named FASS and were previously mentioned in Wikipedia. Further contributions may follow other systems
- ^ Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare)
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:. PMID 14739630.
- Daly AK, Aithal GP (2004). "Genetic regulation of warfarin metabolism and response.". Seminars in vascular medicine 3 (3): 231–8. doi:. 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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