Starvation and phenobarbital treatment effects on drug hydroxylation and glucuronidation in the rat liver and small intestinal mucosa

Abstract

Drug hydroxylation and glucuronidation enzyme levels were measured in the liver and small intestinal mucosa of male rats after starvation for 3 days and after starvation combined with phenobarbital treatment (80 mg/kg, 3 days). After simple starvation liver microsomal cytochrome P-450 content and NADPH cytochrome c reductase activity were unaffected, while p-nitroanisole demethylase activity was increased. Specific activities of the UDPglucose dehydrogenase, total β-glucuronidase and 3-hydroxy-acid dehydrogenase were increased, UDPglucuronosyltransferase was unaffected and glucuronolactone dehydrogenase was decreased. When activities were calculated per whole liver, all enzymes tested were decreased during starvation due to the reduction of the liver weight. In the small intestinal mucosa specific enzyme activities were lower in the starved animals, with the exception of UDPglucuronosyl-transferase which was not changed. The excretion into the urine of d-glucaric and l-ascorbic acid, two final products of the glucuronic acid pathway in the rat, was decreased by fasting. Phenobarbital treatment proved more effective in inducing several enzymes in the starved animals than in those fed ad lib. This compensated for the reduction of total activities due to the loss of liver weight. Despite fasting, the excretion into the urine of d-glucaric and l-ascorbic acid was enhanced after treatment with phenobarbital, and d-glucaric acid reached the levels found in normally fed rats. These findings suggest that starvation impairs drug-metabolism in the rat liver and small intestinal mucosa. Inducibility of the drug-metabolizing enzymes, however, is not depressed by this condition, but on the contrary it is markedly enhanced.