Effects of endotoxin upon rat hepatic microsomal drug metabolism in vivo and in vitro.

Abstract

1. Bacterial endotoxin, a soluble lipopolysaccharide, has been studied to ascertain its effects in vivo and in vitro on the hepatic drug-metabolizing enzymes of adult male and female rats. 2. 24 h after a single 1 X 0 or 2 X 0 mg/kg i.p. dose of endotoxin, hexobarbital sleeping time was significantly increased in adult male rats. Significant inhibition of liver microsomal cytochrome P-450 occurred after 6 h and continued only until 24 h after endotoxin administration, while injection of inactivated endotoxin did not result in any significant decrease of hepatic mixed-function oxidase enzymes or cytochrome P-450. In contrast, rho-nitrophenol-UDP-glucuronyltransferase enzyme activity was unaffected by these levels of endotoxin. 3. Electron-microscopic examination of rat liver hepatocytes did not reveal any significant change in ultrastructure 24 h after a single i.p. dose of endotoxin. 4. Endotoxin failed to depress the phenobarbitone- or 3-methylcholanthrene-induced forms of cytochrome P-450 and the dependent mono-oxygenase enzymes. Simultaneous administration of phenobarbital and endotoxin resulted in 100% mortality of rats. Combination of 3-methylcholanthrene and endotoxin did not block the induction of cytochrome P-448 or dependent benzo[a]pyrene hydroxylase activity. 5. Addition of endotoxin in vitro resulted in significant inhibition of hepatic microsomal cytochrome P-450 and aminopyrine N-demethylase activity only on preincubation with an NADPH-generating system supplemented with EDTA.