Cytochrome P-450
Cytochrome P-450 is a "superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism."[1]
Common abnormal alleles
Isoforms CYP2C9, CYP2C19, and CYP2D6 account for 40% of metabolism by Cytochrome P-450.[2]
CYP2C9
CYP2C9 is an isoenzyme of cytochrome P-450.[3]2-6% of anglos are poor metabolizers of drugs that use the CYP2D6 isoenzyme.[4][5][6]
Polymorphisms of CYP2C9 explain 10% of variation in warfarin dosing[7], mainly among Caucasian patients as these variants are rare in African American and most Asian populations.[8] A meta-analysis of mainly Caucasian patients found[8]:
- CYP2C9*2 allele:
- present in 12.2% of patients
- mean reduction was in warfarin dose was 0.85 mg (17% reduction)
- relative bleeding risk was 1.91
- CYP2C9*3 allele:
- present in 7.9% of patients
- mean reduction was in warfarin dose was 1.92 mg (37% reduction)
- relative bleeding risk was 1.77
CYP2C19
CYP2C19 is an isoenzyme of cytochrome P-450.[9] 2-6% of anglos and 15-25% of asians are poor metabolizers of drugs that use the CYP2D6 isoenzyme.[10][5][6] More recently, a study suggests that 30% of patients may have a reduced-function allele.[11]
CYP2C19 polymorphism affects response to clopidogrel. 30% of patients may have a reduced-function allele.[11]
CYP2D6
3-10% of anglos and < 2% of asians and africans are poor metabolizers of drugs that use the CYP2D6 isoenzyme.[12][5][6]
Poor metabolism affects many antidepressants, metoprolol and other drugs that use this isoenzyme. More information is available at Entrez Gene.[13]
References
- ↑ Anonymous (2024), Cytochrome P-450 (English). Medical Subject Headings. U.S. National Library of Medicine.
- ↑ Caraco Y (December 2004). "Genes and the response to drugs". N. Engl. J. Med. 351 (27): 2867–9. DOI:10.1056/NEJMe048278. PMID 15625340. Research Blogging.
- ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 601130. World Wide Web URL: http://omim.org/.
- ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124030. World Wide Web URL: http://omim.org/.
- ↑ 5.0 5.1 5.2 Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (November 2001). "Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review". JAMA 286 (18): 2270–9. PMID 11710893. [e]
- ↑ 6.0 6.1 6.2 Weinshilboum R (February 2003). "Inheritance and drug response". N. Engl. J. Med. 348 (6): 529–37. DOI:10.1056/NEJMra020021. PMID 12571261. Research Blogging.
- ↑ Wadelius M, Chen LY, Downes K, et al (2005). "Common VKORC1 and GGCX polymorphisms associated with warfarin dose". Pharmacogenomics J. 5 (4): 262-70. DOI:10.1038/sj.tpj.6500313. PMID 15883587. Research Blogging.
- ↑ 8.0 8.1 Sanderson S, Emery J, Higgins J (2005). "CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis". Genet. Med. 7 (2): 97-104. PMID 15714076. [e]
- ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124020. World Wide Web URL: http://omim.org/.
- ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124030. World Wide Web URL: http://omim.org/.
- ↑ 11.0 11.1 Mega JL, Close SL, Wiviott SD, et al (December 2008). "Cytochrome P-450 Polymorphisms and Response to Clopidogrel". N. Engl. J. Med.. DOI:10.1056/NEJMoa0809171. PMID 19106084. Research Blogging.
- ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124030. World Wide Web URL: http://omim.org/.
- ↑ Anonymous. Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6 [ Homo sapiens ]. National Library of Medicine. Retrieved on 2009-01-03.