Transgenic models in xenobiotic metabolism and toxicology

There exist in animals a large number of enzymes that primarily metabolize xenobiotics including drugs, toxins and carcinogens. While these enzymes are known to activate or inactivate toxins and carcinogens in vitro, it had not been demonstrated until recently whether they are responsible for the biological effects of these chemicals in intact animal models. In order to determine the biological affects of xenobiotic-metabolizing enzymes, gene knockout mice were made that lack expression of certain P450s (CYT1A1, CYP1A2, CYP1B1 and CYP2E1), microsomal and cytosolic epoxide hydrolases, and NADPH:quinone oxidoreductase. These mice have no deleterious phenotypes indicating that xenobiotic-metabolizing enzymes have no direct role in mammalian development and physiological homeostasis even though all the genes and enzymes examined are conserved in mammals. However, in many cases, mice lacking certain xenobiotic-metabolizing enzymes confer resistance to acute toxicities and chemical carcinogenesis thus demonstrating that these enzymes mediate the deleterious effects of chemicals. The use of xenobiotic metabolism null animal models to study the mechanisms of actions of toxins and carcinogens will be reviewed. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.