Polymorphism of cytochrome P450 and xenobiotic toxicity.

The majority of human P450-dependent xenobiotic metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively altered or enhanced metabolism. The latter situation is due to stable duplication, multiduplication or amplification of active genes, most likely in response to dietary components that have resulted in a selection of alleles with multiple non-inducible genes. An updated list of variant CYP alleles is present at the Home Page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http://www.imm.ki.se/CYPalleles/). Several examples exist where subjects carrying certain alleles suffer from a lack of drug efficacy due to ultrarapid metabolism or, alternatively, adverse effects from the drug treatment due to the presence of defective alleles. Dosage requirements for several commonly used drugs that have a narrow therapeutic range can differ more than 20-fold dependent on the genotype or the enzyme expression status. By contrast, carcinogen metabolising cytochrome P450s are less polymorphic and no firm relationships have been established linking increased risk for cancer with any specific P450 polymorphism. In the present overview recent aspects of cytochrome P450 polymorphism and xenobiotic toxicity are discussed.