Conjugation of glutathione with the reactive metabolites of 1, 1-dichloroethylene in murine lung and liver.
Exposure to 1,1-dichloroethylene (DCE) elicits lung and liver cytotoxicities that are manifested in bronchiolar Clara cell injury and centrilobular necrosis, respectively. The tissue damage is associated with cytochrome P450-dependent bioactivation of DCE to reactive intermediates, and is consistent with the finding that the target cells coincided with the sites of high concentrations of cytochrome P450 enzymes. The metabolites formed from DCE bind covalently to cellular macromolecules, and the extent of binding and cell damage are inversely related to the content of intracellular glutathione (GSH). Histochemical studies showed that staining for GSH in the lung is localized in the bronchiolar epithelial and alveolar septal cells, with relatively strong staining in the Clara cells. In the liver, staining is observed rather uniformly in hepatocytes distributed across the hepatic lobule. Depletion of GSH correlates with the Clara cell damage and centrilobular necrosis observed in the lung and liver, respectively. The primary metabolites of DCE formed in lung and liver microsomal incubations have been identified as DCE-epoxide, 2,2-dichloroacetaldehyde and 2-chloroacetyl chloride. All are electrophilic metabolites that form secondary reactions including conjugation with GSH. Results of our studies indicated that the DCE-epoxide is the major metabolite forming conjugates with GSH, and this reaction is likely responsible for the depletion of GSH observed in vivo. Our findings support the premise that, following depletion of intracellular GSH, metabolites of DCE including the DCE-epoxide bind to cellular proteins, a process which leads to cell damage and suggests that conjugation with the thiol nucleophile represents a-detoxification mechanism.
Forkert
P G
PG
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada.
D000818:Animals; D001711:Biotransformation; D004000:Dichloroethylenes / Q000493:pharmacokinetics* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D051379:Mice
D004000:Dichloroethylenes; C029297:vinylidene chloride; D005978:Glutathione