Effects of administration of metabolic inducers and inhibitors on pulmonary toxicity and covalent binding by 1,1-dichloroethylene in CD-1 mice.
The administration of 1,1-dichloroethylene (1,1-DCE, 125 mg/kg ip) to CD-1 mice caused bronchiolar necrosis, which was accompanied by substantial covalent binding of radiolabeled compound and/or metabolite to lung. Lung injury and covalent binding were not modified by phenobarbital pretreatment. However, 3-methylcholanthrene provided a protective influence but failed to alter covalent binding to lung macromolecules. Prior administration with the metabolic inhibitors, piperonyl butoxide and SKF 525-A, produced differential effects. While piperonyl butoxide exacerbated bronchiolar injury by 1,1-DCE, covalent binding remained unaltered. In contrast, SKF 525-A protected from lung damage and significantly decreased covalent binding. Hepatic necrosis was relatively mild, and was not observed in all animals treated with 1,1-DCE. Although the hepatic lesion was not modified by phenobarbital, liver injury was slightly diminished by 3-methylcholanthrene. The inducers, piperonyl butoxide and SKF 525-A, enhanced liver necrosis, with the latter eliciting more severe effects than the former agent. Covalent binding to liver tissues was not significantly changed by pretreatment with either inducers or inhibitors. These results indicate that lack of an unequivocal correlation of cellular injury with covalent binding, but suggest that metabolism may be involved in the pneumotoxicity by 1,1-DCE. The influence and modification of lung injury by the liver, however, remain to be further elucidated.
D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000473:pathology; D004000:Dichloroethylenes / Q000633:toxicity*; D004347:Drug Interactions; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D008168:Lung / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D051379:Mice; D008861:Microsomes / Q000187:drug effects; D009336:Necrosis; D010882:Piperonyl Butoxide / Q000494:pharmacology*; D011335:Proadifen / Q000494:pharmacology*; D013997:Time Factors
D004000:Dichloroethylenes; D006843:Hydrocarbons, Chlorinated; C029297:vinylidene chloride; D008748:Methylcholanthrene; D011335:Proadifen; D010882:Piperonyl Butoxide