Reaction of glutathione with the electrophilic metabolites of 1,1-dichloroethylene

doi:10.1016/0009-2797(94)03563-N

Chemico-Biological Interactions

Volume 95, Issue 3, 14 April 1995, Pages 227-244

https://doi.org/10.1016/0009-2797(94)03563-N Get rights and content

Abstract

1,1-Dichloroethylene (DCE) requires cytochrome P450-catalyzed bioactivation to electrophilic metabolites (1,1-dichloroethylene oxide, 2-chloroacetyl chloride and 2,2-dichloroacetaldehyde) to exert its cytotoxic effects. In this investigation, we examined the reactions of these metabolites with glutathione by spectroscopic and Chromatographic techniques. In view of the extreme reactivity of 2-chloroacetyl chloride, primary reactions are likely to include alkylation of cytochrome P450, conjugation with GSH to give S-(2-chloroacetyl)-glutathione, or hydrolysis to give 2-chloroacetic acid. Our results showed conjugation of GSH with 1,1-dichloroethylene oxide, through formation of the mono- and di-glutathione adducts, 2-S-glutathionyl acetate and 2-(S-glutathionyl) acetyl glutathione, respectively. The observed equilibrium constant between the hydrate of 2,2-dichloroacetaldehyde and S-(2,2-dichloro-1-hydroxy)ethylglutathione was estimated from ¹H-NMR experiments to be 14 ± 2 M⁻¹. Thus, 2,2-dichloroacetaldehyde is unlikely to make a significant contribution to GSH depletion as GSH concentrations above normal physiological levels would be necessary to form significant amounts of S-(2,2-dichloro-1-hydroxy)ethylglutathione. We also compared the formation of the glutathione conjugates in rat and mouse liver microsomes using ¹⁴C-DCE. The results demonstrated a species difference; the total metabolite production was 6-fold higher in microsomes from mice, compared with samples from rat. Production of DCE metabolites in hepatic microsomes from acetone-pretreated mice was 3-fold higher than those from untreated mice suggesting a role for P450 2E1 in DCE bioactivation. These results indicate that the epoxide is the major metabolite of DCE that is responsible for GSH depletion, suggesting that it may be involved in the hepatotoxicity evoked by DCE. Furthermore, this metabolite is formed to a greater extent in mouse than in rat liver microsomes and this difference may underlie the enhanced susceptibility found in the former species.

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Reaction of glutathione with the electrophilic metabolites of 1,1-dichloroethylene

Abstract

Cancer Lett.

Chem.-Biol. Interact.

Biochem. Pharmacol.

Exp. Mol. Pathol.

Appl. Pharmacol.

Fundam. Appl. Toxicol.

Toxicol. Lett.

Anal. Biochem.

Exp. Mol. Pathol.

Biochem. Pharmacol.

Anal. Biochem.

Biochem. Pharmacol.

Tissue-mediated mutagenicity of vinylidene chloride and 2-chlorobutadiene in Salmonella typhimurium

Nature

Carcinogenicity bioassays of vinylidene chloride. Research plan and early results

Med Lavoro

Vinylidine chloride. International programme on chemical safety, Environ

Health Criter.

1,1-Dichloroethylene-induced pulmonary injury

Exp. Lung Res.

1,1-Dichloroethylene hepatotoxicity: proposed mechanism of action and distribution and binding of 14C radioactivity following inhalation exposure in rats

Environ. Health Perspect.

1,1-Dichloroethylene elicits dose-dependent alterations in covalent binding and glutathione in murine liver

Drug Metab. Dispos.

Formation of glutathione conjugates by reactive metabolites of vinylidene chloride in microsomes and isolated hepatocytes

Cancer Res.

1,1-Dichloroethylene-induced alterations in glutathione and covalent binding in murine lung: morphological, histochemical and biochemical studies

J. Pathol.

1,1-Dichloroethylene hepatotoxicity: proposed mechanism of action and distribution and binding of ¹⁴C radioactivity following inhalation exposure in rats