An investigation of the role of microsomal oxidative metabolism in the in vivo genotoxicity of 1,2-dichloroethane.
In vitro studies have demonstrated that two different metabolic pathways, glutathione conjugation mediated by the glutathione S-transferases and microsomal oxidation, may be involved in the genotoxicity and carcinogenicity of 1,2-dichloroethane (DCE). To evaluate the importance of microsomal oxidative metabolism in the bioactivation of DCE in vivo, male B6C3F1 mice were pretreated with piperonyl butoxide (PIB), an inhibitor of microsomal oxidative metabolism, and the effect of this pretreatment on the extent of hepatic DNA damage produced by DCE was determined 4 hr after DCE administration. The in vivo genotoxicity of 2-chloroethanol, a product of the microsomal oxidative metabolism of DCE, was also investigated. Hepatic DNA damage was measured with a sensitive, alkaline DNA unwinding assay for the presence of single-strand breaks and alkali-labile lesions in DNA. Pretreatment of mice with PIB to inhibit microsomal oxidative metabolism significantly potentiated the hepatic DNA damage observed 4 hr after a single, 200-mg/kg, ip dose of DCE. Treatment of mice with single, ip doses of 2-chloroethanol as high as 1.2 mmol/kg failed to produce any evidence of single-strand breaks and/or alkali-labile lesions in hepatic DNA. When diethyl maleate (DEM) was used to deplete hepatic glutathione levels prior to administration of 2-chloroethanol, the acute hepatotoxicity of 2-chloroethanol was potentiated but again there was no evidence of hepatic damage. These results indicate that microsomal, oxidative metabolism of DCE to 2-chloroethanol and/or 2 chloroacetaldehyde is not responsible for the hepatic DNA damage observed in these studies after DCE administration.
D000818:Animals; D004247:DNA / Q000378:metabolism; D004357:Drug Synergism; D005023:Ethylene Chlorohydrin / Q000633:toxicity; D005025:Ethylene Dichlorides / Q000633:toxicity*; D005978:Glutathione / Q000032:analysis; D006591:Hexobarbital / Q000494:pharmacology; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D009153:Mutagens / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010882:Piperonyl Butoxide / Q000494:pharmacology*; D012890:Sleep / Q000187:drug effects
D005025:Ethylene Dichlorides; D006843:Hydrocarbons, Chlorinated; D009153:Mutagens; C024565:ethylene dichloride; D005023:Ethylene Chlorohydrin; D004247:DNA; D006591:Hexobarbital; D005978:Glutathione; D010882:Piperonyl Butoxide