Metabolism of p-nitroanisole and aniline in isolated hepatocytes of streptozotocin-diabetic rats.

The metabolism of p-nitroanisole and aniline was studied in isolated hepatocytes of male and female rats rendered diabetic with streptozotocin. In cells of male diabetic rats the production of the oxidized metabolites of both substrates was decreased relative to cells of control rats. In contrast, enzyme activity toward both substrates was increased when isolated microsomes of diabetic males were studied. Cytochrome P-450 content was increased in hepatocytes and microsomes of these animals. Treatment of diabetic male rats with insulin returned drug disposition and cytochrome P-450 in hepatocytes to control levels. In females, production of oxidized metabolites in hepatocytes as well as mono-oxygenase activities in microsomes were increased by diabetes, whereas cytochrome P-450 levels were not significantly altered in hepatocytes or microsomes. The results indicate that the effect of diabetes on drug metabolism observed in microsomal preparations may not accurately reflect the pattern of drug disposition in the whole cell. The pattern may ultimately be determined by other factors within the hepatocytes which are altered in the diabetic condition. Such factors may be responsible for the sex-dependent effects of streptozotocin diabetes on drug metabolism in rat hepatocytes.