© 1987 Oxford University Press
research-article |
Modulation of monocrotaline-induced hepatic genotoxicity in rats
University of Arizona, Department of Pharmacology and Toxicology Tucson, AZ 85721, USA
1Present address: National Institute of Health, National Institute of Environmental Health Sciences, Laboratory of Molecular Biophysics Research Triangle Park, NC 27709, USA
2To whom correspondence should be sent
Monocrotaline (MCT), a hepatotoxic/hepatocarcinogenic pyr-rolizidine alkaloid (PA) induced DNA-DNA interstrand crosslinks in a dose-dependent manner through 30 mg/kg. Hepatic cytochrome P-450 has been shown to bioactivate MCT to pyrrole derivatives which are thought to be respons-ible for these genotoxic lesions. We have hypothesized these lesions to be related to the adverse hepatic actions of MCT and other PAs. Studies reported here investigated the effect of phenobarbital, a P450 inducer, 2-dimethylaminoethyl-2,2- diphenylvalerate, a P450 inhibitor and butylated hydroxy anisole, a dietary antioxidant, on hepatic DNA-DNA interstrand cross-links induced by a single dose of MCT (15 mg/kg i.p.) administered to male Sprague-Dawley rats. DNA damage was assessed by alkaline elution. The effects of these pretreatment regimens on MCT-induced DNA-DNA interstrand cross-linking was qualitatively similar to their reported effects on the hepatotoxicity of MCT. The effects of these pretreatments on hepatic cytochrome P-450 content, hepatic non-protein sulfliydryl levels and hepatic glutathione S-transferase activities were similarly investigated in attempts to explain the observed effects on DNA cross-link induction. These data provide further support for the association between DNA damage and the adverse hepatic effects of MCT.