Pharmacogenetics of the Cytochrome P450 Enzyme System: Review of Current Knowledge and Clinical Significance

Abstract

Genetic variation in drug metabolizing enzymes is an important contributor to interindividual variation in drug disposition and response and is associated with significant clinical consequences. Many commonly used drugs are dependent on the cytochrome P450 monooxygenase enzymes (CYP450) for their metabolism and elimination. At present, more than 57 active human CYP450 genes are known, and the majority of these genes are polymorphic. Despite the large number of CYP450 genes, only the CYP1, CYP2, and CYP3 families of enzymes have a major role in drug metabolism. Approximately 10 CYP450s are responsible for the metabolism of a large number of pharmacologic agents in human beings. The polymorphic forms of the CYP450s are responsible for the development of a significant number of adverse drug reactions and may also contribute to drug response. Genetic polymorphisms have now been identified in the genes encoding all the main CYP450s that contribute to drug and other xenobiotic metabolism, and there are marked interethnic differences in the distribution and frequency of variant alleles. A review of the progress in the pharmacogenetics of P450s that are important for drug metabolism is presented with particular emphasis on the clinical relevance of this research.