The role of cytochrome P450 enzymes in hepatic and extrahepatic human drug toxicity.

The human cytochrome P450 enzyme system metabolises a wide array of xenobiotics to pharmacologically inactive metabolites, and occasionally, to toxicologically active metabolites. Impairment of cytochrome P450 activity, which may be either genetic or environmental, may lead to toxicity caused by the parent compound itself. In practise, this usually only applies to drugs that have a narrow therapeutic index and when their clearance is critically dependent upon the fraction normally metabolised by that pathway. P450 enzymes may also convert the drug to a chemically reactive metabolite, which, if not detoxified, may lead to various forms of hepatic and extrahepatic toxicity, including cellular necrosis, hypersensitivity, teratogenicity, and carcinogenicity, depending on the site of formation and the relative stability of the metabolite, and the cellular macromolecule with which it reacts. Variation in the regulation and expression of the drug metabolising enzymes may play a key role in both interindividual variation in sensitivity to drug toxicity and tissue-specific damage. Avoidance of toxicity may be possible in rare instances by prediction of individual susceptibility or by designing new chemical entities that are metabolised by a range of enzymes (both cytochromes P450 and others) and do not undergo bioactivation.