The study of xenobiotic-metabolizing enzymes and their role in toxicity in vivo using targeted gene disruption

Abstract

Most of the chemicals that cause toxicity in animals are metabolized and this metabolism can either increase or decrease the extent of toxicity. A large number of enzymes are involved in the metabolism of xenobiotics. Cytochromes P450 are among the most important and these enzymes are primarily involved in metabolic activation through oxidative metabolism. Transferases, including the glutathione S-transferases, N-acetyltransferases, UDP-glucuronosyltransferases, microsomal and cytosolic epoxide hydrolases, and NAD(P)H quinone oxidoreductase are also significant in xenobiotic metabolism and can play a role in chemical sensitivities. Polymorphisms in P450s and transferases have been found in experimental animals and humans in which a certain segment of the population, usually greater than 1%, are lacking expression of a particular enzyme. In humans, polymorphisms have been associated with adverse drug reactions but have not been shown to cause any serious developmental or physiological defects thus suggesting that in mammals, xenobiotic-metabolizing enzymes may only be required for metabolism of foreign chemicals and have no other critical role. To determine the roles of xenobiotic-metabolizing enzymes in mammalian development and physiological homeostasis, and in sensitivities to chemical toxicity and carcinogenesis, targeted gene disruption was carried out to produce gene knockout mice. Several lines of mice were produced and characterized and these are discussed.