Cytoprotective effects of modulators of oxidative xenobiotic metabolism in precocene II-induced hepatotoxicity

Abstract

This investigation was conducted to evaluate the effects of modulation of several phase I xenobiotic-metabolizing enzyme activities on the expression of precocene II-induced hepatotoxicity. Precocene II (175–200 mg/kg) was given intraperitoneally to male Sprague-Dawley rats that had been exposed previously to inducers (phenobarbital and 3-methylcholanthrene) or inhibitors (SKF 525-A and cimetidine) of oxidative xenobiotic metabolism. Hepatic damage was measured both biochemically (leakage of aspartate aminotransferase and alanine amino-transferase into the serum) and histologically. Significant protection from precocene II-induced hepatotoxicity was observed in all treated animals regardless of whether the modulator employed was an inducer or an inhibitor of microsomal oxidative enzymes. These results indicate that the level of activity of various forms of cytochrome P-450 significantly influences the severity of hepatic necrosis induced by precocene II. Furthermore, these results suggest that inducible non- P-450 factors, such as glutathione S-transferases, may be important in modulating precocene II-induced hepatotoxicity.