FUNDAMENTAL AND APPLIED TOXICOLOGY 29, 147-154 (1996) Article No. 0016 Biochemical Effects of the Mouse Hepatocarcinogen Oxazepam: Similarities to Phenobarbital

The National Toxicology Program (NIF) recently determined that the commonly prescribed sedative hypnotic agent oxazepam is a mouse liver carcinogen. Many other benzodiazepines are me-tabolized to oxazepam resulting in further human exposure to this drug. This has resulted in considerable interest in the mechanism of oxazepam-mediated mouse liver carcinogenesis for use in hu-man risk assessment. Several directions for mechanistic research were examined in this study. B6C3F1 mice were treated with oxaz-epam-dosed feed at 125 (noncarcinogenic) and 2500 ppm (carcino-genic) for 3, 7, 10, and 21 days. Cell proliferation in liver, cyto-chrome P450 induction, free radical formation, GSH depletion, and levels of circulating thyroid-stimulating hormone (TSH) were analyzed at these time points. Increased levels of hepatic cell pro-liferation were observed by 7 days at 125 ppm and by 10 days at 2500 ppm. Microsomal enzyme induction also occurred and wa