- Discuss relevant genetic polymorphisms of important CYPs.
- Outline potential ethnic and racial differences in CYP genetics.
- Discuss potential clinical implications of genetic polymorphism.
Cytochrome P450s (CYPs) are a heme-containing superfamily of enzymes responsible for the metabolism of a wide range of structurally diverse substrates. In addition to the metabolism of human drugs, they also have biologically important roles, such as metabolism of several hormones, synthesis and elimination of cholesterol, regulation of blood homeostasis, metabolism of arachidonic acid, and detoxification of foreign pollutants. Genetic polymorphisms in genes encoding drug-metabolizing enzymes can result in variability in drug metabolism and drug elimination, which often affect treatment outcome at various degrees, depending on the severity of mutation and the extent of penetrance of that gene. There are large environmental factors, drug–drug interactions, and clinical factors that influence clinical outcomes, providing further complexity in understanding individual differences in drug responses. Because CYPs play a critical role in the metabolism of human drugs, accounting for approximately 80% of all phase I drug metabolism, CYP genes have been important targets for pharmacogenetics and pharmacogenomics research. Tremendous efforts on pharmacogenetics and pharmacogenomics during the last several decades have led to the discovery of many clinically relevant genetic polymorphisms in CYPs. This chapter presents an overview of functional CYP polymorphisms with regard to biochemical aspects as well as clinical consequences.
Among the four CYP2C genes in humans, CYP2C9 is the most abundantly expressed enzyme in the human liver,1,2 accounting for the metabolism of approximately 15–20% of prescribed and over-the-counter drugs.3 CYP2C9 metabolizes a number of clinically important drugs, including the antidiabetic drugs tolbutamide and glipizide,4,5 the anticonvulsant phenytoin,6 the anticoagulant warfarin,7 the antihypertensive drug losartan,8 the diuretic torasemide,9 and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, diclofenac, piroxicam, tenoxicam, and mefenamic acid.10 CYP2C9 also metabolizes endogenous substrates, such as arachidonic acid and linoleic acid.11 Since CYP2C9 is polymorphic, it is involved in interindividual variation in the metabolism and disposition of the drugs described above. In particular, drugs with a narrow therapeutic index, such as S-warfarin and phenytoin, can present serious problems in dose adjustments while achieving appropriate drug concentrations without causing high dose–induced drug toxicity.
Functional Polymorphism of CYP2C9
A number of polymorphisms of CYP2C9 have been shown to contribute to altered CYP2C9 activity. The two most prevalent and clinically relevant defective variants in white populations are CYP2C9*2 and *3.12–15 Null variant alleles include CYP2C9*6, *15, and *25.16–18 CYP2C9 variants identified from phenotyped individuals include CYP2C9*2, *3, *4, *5, *6, *11, *13, and *1419–22 (Figure 6A–1). The frequency of CYP2C9*2 is 11% in whites and about 1% in blacks.23,24 However, the frequency of CYP2C9*2 in Asians is very rare or not detected in certain populations, such ...