How knockout mouse lines will be used to study the role of drug-metabolizing enzymes and their receptors during reproduction and development, and in environmental toxicity, cancer, and oxidative stress

The dioxin-inducible mouse [Ah] battery contains at least six genes that ''cross-talk'' with one another and are believed to play important roles in reproduction and development, and in environmental toxicity, cancer, and oxidative stress. In addition to two P450 genes, Cypla1 and Cypla2, this laboratory has shown that the lour Phase II [Ah] genes include: NAD(P)H:menadione oxidoreductase (Nmol); a cytosolic ''class 3'' aldehyde dehydrogenase (Ahd4); a LTDP glucuronosyltransferase having 4-methylumbelliferone as substrate (Ugt1a6); and a glutathione transferase having 2,4-dinitro-1-chlorobenzene as substrate (Gsta1, Ya). The Ah receptor-mediated coordinate induction is controlled positively in all six [Ah] battery genes. Oxidative stress up-regulates the four Phase II [Ah] genes. This laboratory is generating conventional, plus inducible, knockout mouse lines having homozygous disruptions in the above-mentioned genes; this novel methodology is described herein. Ii the conventional knockout is healthy and viable, the mouse line would be useful for studies involving environmental agents. If the conventional knockout is lethal during development, this model would be important for developmental biology, but the inducible (also called conditional) knockout can still be used-at selected ages and even in selected tissue or cell types-for studies designed to understand the mechanisms involved in reproduction and development, and in environmental toxicity, cancer, and oxidative stress. Copyright (C) 1997 Elsevier Science Inc.