Induction of strand breaks in DNA by trichloroethylene and metabolites in rat and mouse liver in vivo.
The ability of trichloroethylene (TCE) and selected metabolites to induce single-strand breaks in hepatic DNA of male B6C3F1 mice and Sprague-Dawley rats in vivo was evaluated using an alkaline unwinding assay. Doses of TCE of 22-30 mmol/kg were required to produce strand breaks in DNA in rats, whereas a dose of 11.4 mmol/kg was sufficient to increase the rate of alkaline unwinding in mice. To assess the importance of TCE metabolism to this response, rats were subjected to pretreatments of ethanol, phenobarbital, TCE, or the appropriate vehicle for 4 days prior to challenge doses of TCE. Phenobarbital and TCE, but not ethanol pretreatments, reduced the dose of TCE required to produce significant increases in single-strand breaks. In another series of experiments, mice and rats were treated with metabolites of TCE. Trichloroacetate, dichloroacetate, and chloral hydrate induced strand breaks in hepatic DNA in a dose-dependent manner in both species. Strand breaks in DNA were observed at doses that produced no observable hepatotoxic effects as measured by serum aspartate aminotransferase and alanine aminotransferase levels. The slopes of the dose-response curves and the order of potency of these metabolites differed significantly between rats and mice, suggesting that different mechanisms of single-strand break induction may be involved in the two species. These data provide a potential explanation for the different sensitivity of mice and rats to the hepatocarcinogenic effects of TCE.
Nelson
M A
MA
Pharmacology/Toxicology Graduate Program, College of Pharmacy, Washington State University, Pullman 99164-6510.
Bull
R J
RJ
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001711:Biotransformation; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014241:Trichloroethylene / Q000378:metabolism / Q000633:toxicity*
D014241:Trichloroethylene; D000431:Ethanol; D004247:DNA; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D010634:Phenobarbital