Dietary cholesterol-induced changes of xenobiotic metabolism in liver. II. Effects of phenobarbitone and carbon tetrachloride on activities of drug-metabolizing enzymes.

: The influence of dietary cholesterol on drug metabolism was studied by feeding rats either a cholesterol-free or a high (2%) cholesterol diet for 4 weeks from weanling onward and giving phenobarbitone (Pb) and/or carbon tetrachloride (CCl4) thereafter. Pb was given in drinking water for 7 days at a dosage of 100 mg/kg and CCl4, at a dosage of 1.5 mg/kg SC 6 days before assays of drug-metabolizing enzymes. The cytochrome P-450 concentration was 2-fold in rats fed the 2% cholesterol diet in comparison with those fed the cholesterol-free diet. Only a weak induction by Pb was found in the cholesterol-free group. Only slight differences due to the cholesterol diets or due to the administration of xenobiotics were found in the NADPH cytochrome c reductase activity. The PPO hydroxylase activity was 2-fold in the livers of rats fed the 2% cholesterol diet in comparison with those fed the cholesterol-free diet. In the ethoxyresorufin deethylase activity, differences between diets were present first after the administration of xenobiotics. No change in the hepatic aryl hydrocarbon hydroxylase activity was found due to changes in the cholesterol content of the diets. The ethoxycoumarin O-deethylase activity was 2-fold in the livers of rats fed 2% cholesterol diet from those fed the cholesterol-free diet. The inducibility of ethoxycoumarin O-deethylase was equal, regardless of which diet was used. The hepatic epoxide hydrolase activity of rats fed 2% cholesterol was 3-fold in comparison with the cholesterol-free group. The inducibility by Pb was higher in the livers of the cholesterol-free (3.3-fold) than 2% cholesterol-fed rats (2.4-fold). The hepatic UDP-glucuronosyl-transferase activity was 1.5-fold in 2% cholesterol-fed rats in comparison with rats fed the cholesterol-free diet. The inducibility by CCL4 was found only in rats fed the cholesterol-free diet. The results suggest that dietary cholesterol modifies the enzyme activities in the liver and modifies their response to enzyme inducers.