The cytochrome P450-dependent monooxygenase system is responsible for the majority of oxidation reactions of drugs and other xenobiotics. Variations in these biotransformation activities may alter the bioavailability or efficacy of drugs, provide protection from certain xenobiotic agents, or increase toxicity of others. A mutation in the obese gene in the C57BL/6J mouse results in the mutant obese mouse (ob/ob), which displays several altered physiological conditions. The present research reports on the hepatic microsomal cytochrome P450-dependent activities, glutathione transferase activity, and expression in liver of selected P450 mRNAs in the ob/ob mouse at 3-4 months (young) and 7-8 months (old) of age. CYP2E1- and CYP3A-dependent activities were measured by p-nitrophenol hydroxylase and erythromycin demethylase, respectively. Activities for CYP1A1/1A2, CYP3A and CYP2B were estimated by determining O-deakylation of ethoxy-, benzoxy- and pentoxyresorufin, respectively. Female mice, regardless of age, showed an obesity enhanced level of CYP2E1-dependent activity and protein as shown by Western blots. The mRNA level of CYP2E1 in female mice did exhibit age and obesity-influenced differences in expression. No significant differences in CYP2E1-dependent activity or expression were observed in male mice. CYP3A-dependent activity was significantly higher in young males, regardless of phenotype. Benzoxy-and pentoxy-resorufin dealkylase activities did not differ among any animals; however, ethoxy-resorufin dealkylase activity, while depressed in obese animals of both sexes, were significantly different in old animals. Glutathione transferase activity was lowered in obese male mice, whereas no difference was reported between lean and obese females.
The Toxicologist. Society of Toxicology 35th Annual Meeting, March 10-14,1996, Anaheim, California