INFLUENCE OF INDUCERS AND INHIBITORS OF CYTOCHROME-P450 ON THE HEPATOTOXICITY OF HYDRAZINE IN-VIVO

Hydrazine hepatotoxicity in vivo, as manifested by triglyceride accumu lation, depletion of ATP and reduced glutathione (GSH) was shown to be dose related. The effect of pretreatment of rats with various inhibit ors and inducers of cytochrome P450 on these dose-response relationshi ps was investigated. Pretreatment with the inhibitor piperonyl butoxid e increased triglyceride accumulation whereas pretreatment with the in ducers phenobarbital and P-naphthoflavone (BNF) resulted in reduced tr iglyceride accumulation. Pretreatment with the inducers acetone and is oniazid also enhanced triglyceride accumulation. Only phenobarbital pr etreatment also significantly reduced GSH and ATP depletion. A linear correlation was found between hepatic glutathione and ATP levels in no n-pretreated animals given various doses of hydrazine. However, expone ntial relationships were found between hepatic triglycerides and both hepatic ATP and glutathione. The results suggest that i) the hepatotox icity of hydrazine can be modulated by inducing or inhibiting particul ar isoenzymes of cytochrome P450, ii) ATP and GSH depletion may not be directly involved in the development of fatty liver.