Abstract

Numerous investigators have reported abnormalities of hepatic drug metabolism in hypoinsulinemic animal models with chemically induced diabetes mellitus, but there has been little assessment of hepatic drug metabolism in recently described animal models with genetic diabetes mellitus characterized by hyperinsulinemia and insulin resistance rather than insulin deficiency. Hepatic microsomal cytochrome P-450 content and drug metabolizing activity in obese, diabetic C57BL/KsJ mice homozygous for the diabetes gene mutation (db/db) have been compared with levels found in livers of 1) lean, nondiabetic control mice with the same C57BL/KsJ genetic background and 2) lean C57BL/6J animals made diabetic by streptozotocin treatment. No changes in specific enzyme content or activity were seen in young db/db mice, but microsomal protein and total hepatic cytochrome P-450 content and meperidine demethylation and pentobarbital hydroxylation activity were markedly increased compared to controls. In hyperglycemic, hypoinsulinemic mice with streptozotocin-induced diabetes mellitus, the amount of microsomal protein did not change, but hepatic cytochrome P-450 content and enzyme activity were significantly increased whether expressed per milligram of microsomal protein or as totals per liver. In old db/db animals, hyperglycemia persisted but plasma insulin levels fell into the normal range so that the insulin-glucose profile of these animals resembled that seen in the streptozotocin treatment group. In association with these changes, hepatic enzyme specific activities in the old db/db mice approximated values found in the streptozotocin group rather than in the young db/db animals. These differences in hepatic microsomal enzymes between hyperinsulinemic and hypoinsulinemic mice with diabetes mellitus suggest that both hyperglycemia and insulin separately and significantly influence cytochrome P-450 turnover and mixed function oxidase activity.