In vitro hepatic drug metabolism and microsomal enzyme induction in genetically obese rats

Abstract

Genetically obese Zucker-strain rats were used to determine if obesity produced alterations in in vitro drug metabolism in hepatic microsomes or cytosol. Adult homozygous obese rats of both sexes had significantly less active drug-metabolizing enzymes in vitro than homozygous lean Zucker rats or Sprague-Dawley rats. Specific activities of aniline hydroxylase, aminopyrine demethylase and arylhydrocarbon hydroxylase (AHH) from male obese rats were only 25–30 percent of control activities, while glutathione S-aryltransferase, biphenyl 4-hydroxylase, and cytochrome P-450 activities were 50–70 percent of control activities. K m and V max values for aminopyrine demethylation were significantly less in obese rats than in lean rats. Enzyme activities in weanling obese rats were nearly equivalent to activities in weanling lean rats. Pretreatment of obese and lean rats with 3-methylcholanthrene produced expected increases in activities of biphenyl 4-hydroxylase, AHH and cytochrome P-450. Phenobarbital (PB), however killed half of the PB-treated obese rats at 60 mg/kg, but killed no lean rats. At lower doses, PB pretreatment produced only marginal increases in specific activities of aniline hydroxylase, aminopyrine demethylase and cytochrome P-450 in obese rats, while producing larger increases in activities in lean controls. When genetically obese rats were pair-fed to body weights that were equal to lean rats, the deficiency in in vitro drug metabolism between lean and fat rats was qualitatively as great as in ad lib. fed rats. Testosterone treatment of obese rats produced no significant increase in in vitro drug metabolism. Heterozygous lean Zucker rats responded to all treatments in a manner similar to that of homozygous lean Zucker rats. The explanation for these results is complex and they cannot be accounted for by a simple increase in body weight.