Influence of inducers and inhibitors of cytochrome P450 on the hepatotoxicity of hydrazine in vivo

Hydrazine hepatotoxicity in vivo, as manifested by triglyceride accumulation, depletion of ATP and reduced glutathione (GSH) was shown to be dose related. The effect of pretreatment of rats with various inhibitors and inducers of cytochrome P450 on these dose-response relationships was investigated....

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Bibliographic Details
Published inArchives of toxicology Vol. 68; no. 6; p. 349
Main Authors Jenner, A M, Timbrell, J A
Format Journal Article
LanguageEnglish
Published Germany 01.06.1994
Subjects
Acetone - pharmacology
Adenosine Triphosphate - metabolism
Animals
Benzoflavones - pharmacology
beta-Naphthoflavone
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System - biosynthesis
Cytochrome P-450 Enzyme System - drug effects
Enzyme Induction - drug effects
Glutathione - metabolism
Hydrazines - metabolism
Hydrazines - toxicity
Isoniazid - pharmacology
Liver - drug effects
Liver - metabolism
Male
Phenobarbital - pharmacology
Piperonyl Butoxide - pharmacology
Rats
Rats, Sprague-Dawley
Triglycerides - metabolism
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Summary:Hydrazine hepatotoxicity in vivo, as manifested by triglyceride accumulation, depletion of ATP and reduced glutathione (GSH) was shown to be dose related. The effect of pretreatment of rats with various inhibitors and inducers of cytochrome P450 on these dose-response relationships was investigated. Pretreatment with the inhibitor piperonyl butoxide increased triglyceride accumulation whereas pretreatment with the inducers phenobarbital and beta-naphthoflavone (BNF) resulted in reduced triglyceride accumulation. Pretreatment with the inducers acetone and isoniazid also enhanced triglyceride accumulation. Only phenobarbital pretreatment also significantly reduced GSH and ATP depletion. A linear correlation was found between hepatic glutathione and ATP levels in non-pretreated animals given various doses of hydrazine. However, exponential relationships were found between hepatic triglycerides and both hepatic ATP and glutathione. The results suggest that i) the hepatotoxicity of hydrazine can be modulated by inducing or inhibiting particular isoenzymes of cytochrome P450, ii) ATP and GSH depletion may not be directly involved in the development of fatty liver.
ISSN:0340-5761
1432-0738
DOI:10.1007/s002040050081