Mechanisms of 1,1-dichloroethylene-induced cytotoxicity in lung and liver.
Exposure to 1,1-dichloroethylene (DCE) causes lung and liver toxicities in mice. The lesions are characterized by damage preferentially to bronchiolar Clara cells in the lung and necrosis of centrilobular hepatocytes in the liver. The primary metabolites formed from DCE in lung and liver microsomal incubations are the epoxide, 2,2-dichloroacetaldehyde and 2-chloroacetyl chloride, which undergo hydrolysis and/or conjugation with glutathione (GSH). The major products formed are the epoxide-derived GSH conjugates 2-(S-glutathionyl) acetyl glutathione [B] and 2-S-glutathionyl acetate [C]. The hydrate of 2,2-dichloroacetaldehyde (acetal) is also detected. These metabolites are detected in vivo in murine lung and liver cytosol and in bile, and importantly, also in human lung and liver microsomal incubations. Formation of the epoxide is mediated mainly by CYP2E1. Immunohistochemical studies localized the epoxide-derived GSH conjugate [C] and cysteine-containing proteins in Clara cells and centrilobular hepatocytes. These findings are consistent with the premise that the lung and liver cytotoxicities induced by DCE are associated with in situ formation of the epoxide within the target cells.
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada.
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D000818:Animals; D001426:Bacterial Proteins; D004000:Dichloroethylenes / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000473:pathology; D014157:Transcription Factors
D001426:Bacterial Proteins; C112951:ClaR protein, Streptomyces clavuligerus; D004000:Dichloroethylenes; D014157:Transcription Factors; C029297:vinylidene chloride