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 cytotoxi cities that are manifested in bronchiolar Clara cell injury and centri lobular necrosis, respectively. The tissue damage is associated with c ytochrome P450-dependent bioactivation of DCE to reactive intermediate s, 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 macromolecule s, 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 bronchiol ar epithelial and alveolar septal cells, with relatively strong staini ng in the Clara cells. In the liver, staining is observed rather unifo rmly in hepatocytes distributed across the hepatic lobule. Depletion o f 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 iden tified as DCE-epoxide, 2,2-dichloroacetaldehyde and 2-chloroacetyl chl oride. 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 obser ved in vivo. Our findings support the premise that, following depletio n of intracellular GSH, metabolites of DCE including the DCE-epoxide b ind to cellular proteins, a process which leads to cell damage and sug gests that conjugation with the thiol nucleophile represents a-detoxif ication mechanism. (C) 1997 Wiley-Liss, Inc.