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Abstract-The drug metabolizing activity of rat liver during long-term adminis tration of carbon tetrachloride (CC14), and its relationship with the content of hydroxyproline (Hyp) in the liver were examined. The contents of cytochrome P-450 (P-450) and cytochrome b5 (b5) and the metabolization of aniline, aminopyrine, 7-ethoxycoumarin (7-EC) and benzo(a)pyrene (B(a)P) in the microsomal fraction were examined five days after the final administration of CC14. The contents of P-450 and b5 and the activity to metabolize the four substrates were gradually reduced as the Hyp content in the liver increased. However, aminopyrine N-demethylation and B(a)P hydroxylation, particularly the latter, was more reduced than aniline hydroxylation and 7-EC 0-deethylation in the early stage of hepatic fibrosis. Such differences may be due mainly to the different P-450 subtypes affected by CC14.

Abstract-The effects of H2-antagonists on acetaminophen-induced hepatic injury were examined.Rats were administered acetaminophen at the dose of 800 mg/kg body, 60 hr after injection of 3-methylcholanthrene.As an H2-antagonist, cime tidine (200 mg/kg), ranitidine (50 mg or 100 mg/kg), or famotidine (20 mg or 40 mg/kg) was administered before and after acetaminophen injection. The group administered only acetaminophen had been severely damaged as evaluated by changes in serum transaminase, P-450 content, aminopyrine demethylation, glutathione content and histological study, but administration of 200 mg cimetidine together with acetaminophen significantly reduced the hepatic injury to nearly the control level. Ranitidine had no protective effect against hepatic injury at the dose of 50 mg, which appears to have the same antacid effect as 200 mg cimeitdine, whereas it had a slight but significant protective effect as evaluated by the trans aminase level, glutathione content and histological study at the dose of 100 mg. Famotidine had no effect against acetaminophen induced hepatic injury. Because famotidine had no effect, the protection by H2-antagonist against acetaminophen induced hepatic injury cannot be explained by the decrease in hepatic blood flow alone. Therefore, inhibition of P-450 activity seems to be more important for reducing the generation of the reactive metabolites of acetaminophen than hepatic blood flow decrease.

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