title: Differential formation of 1,1-dichloroethylene-metabolites in the lungs of adult and weanling male and female mice: correlation with severities of bronchiolar cytotoxicity.
abstract: The bronchiolar Clara cell cytotoxicant, 1,1-dichloroethylene (DCE), is selectively metabolized by CYP2E1 to metabolites including 2,2-dichloroacetaldehyde and DCE-epoxide. We have performed comparative studies in the lungs of adult and weanling male and female mice to determine their relative capacities to metabolize DCE. Levels of activities of p-nitrophenol hydroxylase, N-nitrosodimethylamine demethylase and NADPH-cytochrome P450 reductase were all significantly higher in adult female mice than in either adult male or weanling mice of both sexes. The quantities of 2,2-dichloroacetaldehyde (identified as its hydrolysis product, acetal) and the DCE-epoxide (identified as the GSH conjugates, 2-(S-glutathionyl) acetyl glutathione [B] and 2-S-glutathionyl acetate [C]) formed were significantly higher in lung microsomes from adult female mice than in those from either adult male or weanling mice of both sexes. Also, the metabolite levels formed in weanling mice were significantly higher than in adult male mice. The amounts of DCE-metabolites produced correlated with the relative severities of DCE-induced bronchiolar damage. The severities of bronchiolar injury were in the rank order adult female > weanling male and female > adult male mice, and coincided with the rank order of DCE-epoxide formation in these experimental groups of mice. In comparison with adult male and weanling male and female mice, adult female mice expressed highest levels of activities of CYP2E1-selective and reductase enzymes, formed most of the DCE-epoxide and were most susceptible to DCE-induced pneumotoxicity. These findings demonstrated sex-related differences in expression of activating enzymes and DCE metabolism in lung, and only in the adult female vs. female weanling mice were there age-related effects in regard to formation of both DCE-metabolites and cytotoxicity.
authors.affiliation: Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada.
authors.forename: P G
authors.initials: PG
authors.lastname: Forkert
authors.forename: T F
authors.initials: TF
authors.lastname: Dowsley
authors.forename: R P
authors.initials: RP
authors.lastname: Lee
authors.forename: J Y
authors.initials: JY
authors.lastname: Hong
authors.forename: J B
authors.initials: JB
authors.lastname: Ulreich
mesh_terms: D000818:Animals; D001980:Bronchi / Q000187:drug effects; D002384:Catalysis; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004000:Dichloroethylenes / Q000378:metabolism* / Q000633:toxicity; D005260:Female; D008168:Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism; D014886:Weaning
chemical_list: D004000:Dichloroethylenes; D009603:Nitroso Compounds; C008651:4-nitrosodimethylaniline; C029297:vinylidene chloride; D019392:Cytochrome P-450 CYP2E1