Knockout animals in toxicology: assessment of toxin bioactivation pathwaysusing mice deficient in xenobiotic metabolizing enzymes

Genetically engineered animal models represent a substantial improvement in in vivo assessment of toxic pathways. Several transgenic mouse lines have been designed to detect specific toxic markers in response to xenobiotic ex posure. They are suitable for in vivo large scale screening of potentially toxic effects of drugs and other xenobiotics, and are used as bioassay mode ls for carcinogenicity testing. This contribution will focus on a different strategy, using transgenic knockout mouse lines, to investigate with more accuracy some metabolic pathways leading to the bioactivation or the bioina ctivation of xenobiotics. Through direct knockout of cytochrome P450 (CYP) genes or the knockout of the transcriptional activator of CYP genes AHR (ar yl hydrocarbon receptor), the involvement of hepatic metabolic enzymes in x enobiotic bioactivation will be exemplified. (C) 1998 Elsevier Science Irel and Ltd. All rights reserved.