DIFFERENTIAL FORMATION OF 1,1-DICHLOROETHYLENE-METABOLITES IN THE LUNGS OF ADULT AND WEANLING MALE AND FEMALE MICE - CORRELATION WITH SEVERITIES OF BRONCHIOLAR CYTOTOXICITY

The bronchiolar Clara cell cytotoxicant, 1,1-dichloroethylene (DCE), i s selectively metabolized by CYP2E1 to metabolites including 2,2-dichl oroacetaldehyde 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 fema le mice than in either adult male or weanling mice of both sexes. The quantities of 2,2-dichloroacetaldehyde (identified as its hydrolysis p roduct, acetal) and the DCE-epoxide (identified as the GSH conjugates, 2-(S-glutathionyl) acetyl glutathione [B] and 2-S-glutathionyl acetat e [C]) formed were significantly higher in lung microsomes from adult female mice than in those from either adult male or weanling mice of b oth sexes. Also, the metabolite levels formed in weanling mice were si gnificantly higher than in adult male mice. The amounts of DCE-metabol ites produced correlated with the relative severities of DCE-induced b ronchiolar damage. The severities of bronchiolar injury were in the ra nk order adult female > weanling male and female > adult male mice, an d coincided with the rank order of DCE-epoxide formation in these expe rimental groups of mice. In comparison with adult male and weanling ma le and female mice, adult female mice expressed highest levels of acti vities of CYP2E1-selective and reductase enzymes, formed most of the D CE-epoxide and were most susceptible to DCE-induced pneumotoxicity. Th ese findings demonstrated sex-related differences in expression of act ivating enzymes and DCE metabolism in lung, and only in the adult fema le vs. female weanling mice were there age-related effects in regard t o formation of both DCE-metabolites and cytotoxicity.