Effect of genetic obesity and experimental diabetes on hepatic microsomal mixed function oxidase activities

In male rats, genetic obesity and experimental diabetes are associated with altered activities of several of the hepatic microsomal P-450 isozymes concerned with steroid and xenobiotic oxidation. The present study examined the roles of insulin and ketonaemia in effecting these changes. In obese male Zucker rats, androstenedione 6 beta-, 16 alpha- and 16 beta-hydroxylase activities (mediated by P450PCN-E, P-450UT-A and P450PB-B, respectively) were significantly decreased to 21%, 20% and 43% of lean control. Obesity was also associated with a significant decrease in the activities of N-nitrosodimethylamine demethylase (P-450j) and aniline p-hydroxylase to about 70%. A similar decrease in total microsomal P-450 was also observed. Androstenedione 7 alpha-hydroxylase activity (mediated by P-450UT-F) was unchanged in these animals. In streptozotocin-induced diabetic male Wistar rats, androstenedione 7 alpha- and 16 beta-hydroxylase activities were significantly elevated to 230% and 270% of control, respectively. Significant increases in the rates of N-nitrosodimethylamine demethylase and aniline p-hydroxylase were also noted in diabetic rat liver. In contrast, the activity of P-450UT-A was reduced to 30% of control and P-450PCN-E-specific 6 beta-hydroxylation was unchanged. Control of the diabetic state with insulin treatment reversed all the changes in P-450-mediated activities. Significant correlations were found between serum concentrations of insulin and catalytic activities of P-450PB-B (rho = -0.46), P-450UT-F (rho = -0.65) and P-450j (rho = -0.71). Positive correlations of the same magnitude were also found between these mixed function oxidase activities and beta-hydroxybutyrate.(ABSTRACT TRUNCATED AT 250 WORDS)