Polymorphism in drug metabolism--implications for drug toxicity.

Abstract

Genetic polymorphism of the drug metabolism pathways is commonly encountered both for man and laboratory animal species. It is a major source of variable metabolism and linked events such as response to drugs and toxic substances. In man the cytochrome P-450 isozyme system exhibits considerable polymorphism. Several independent genetic polymorphisms regulating metabolic oxidation at C-, N-, and S-centres have been recently characterised. This phenomenon appears to be a powerful factor in determining biochemical individuality with respect to the oxidative metabolism of drugs and responsiveness to therapeutic agents. Of considerable importance is the recognition of the existence of phenotypes within the individual polymorphism, characterised by an impaired ability to effect metabolic oxidation. Evidence suggests that this factor can determine an increased susceptibility to experience exaggerated pharmacological effects and adverse reactions to several drugs. Laboratory animal species also exhibit polymorphism with respect to several drug metabolic pathways but compared with man, this has been less extensively researched. The study of intra-species differences in metabolism of drugs and toxic substances can be of value: when it occurs it may signal its possible occurrence in man and animal strain models of the human metabolic polymorphisms facilitate the laboratory study of inherited susceptibility to toxicants.