Metabolic activation of 1,1-dichloroethylene by mouse lung and liver microsomes.
1,1-Dichloroethylene (1,1-DCE) causes lung and liver necrosis in mice. Covalent binding of [14C]1,1-DCE to isolated lung and liver microsomes from CD-1 mice required NADPH and was strongly inhibited by carbon monoxide. Lung and liver microsomes isolated from animals treated with phenobarbital demonstrated no changes in covalent binding of [14C]1,1-DCE compared with those from vehicle-treated animals. While 3-methylcholanthrene caused no alterations in binding to lung microsomes, the same pretreatment resulted in significantly increased levels of binding to liver microsomes. Piperonyl butoxide caused significant decreases in covalent binding to lung and liver microsomes; SKF 525-A significantly inhibited binding to liver microsomes but had no effect on lung microsomes. The incubation of liver microsomes with inhibitors required more NADPH than those performed with lung microsomes. The results demonstrate that reactive metabolites of 1,1-DCE can be formed by lung and liver microsomes, and suggest the involvement of cytochrome P-450 isozymes in the lung and liver injury induced by the halocarbon. However, metabolic activation by lung and liver microsomes may additionally involve non P-450 dependent mechanisms as evidenced by relatively high levels of nonspecific binding of 1,1-DCE.
Forkert
P G
PG
Department of Anatomy, Queen's University, Kingston, Ont., Canada.
Hofley
M
M
Racz
W J
WJ
D000818:Animals; D001711:Biotransformation; D002248:Carbon Monoxide / Q000494:pharmacology; D004000:Dichloroethylenes / Q000378:metabolism*; D006843:Hydrocarbons, Chlorinated / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010882:Piperonyl Butoxide / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology
D004000:Dichloroethylenes; D006843:Hydrocarbons, Chlorinated; D009249:NADP; D002248:Carbon Monoxide; D011335:Proadifen; D010882:Piperonyl Butoxide; C035384:1,2-dichloroethylene