Elsevier

Biochemical Pharmacology

Volume 31, Issue 23, 1 December 1982, Pages 3885-3890
Biochemical Pharmacology

Glutathione-dependent reductive dehalogenation of 2,2′,4′-trichloroacetophenone to 2′,4′-dichloroacetophenone☆

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Abstract

α-Haloketones are highly reactive compounds, which are known to undergo enzymatic reduction to methyl ketones. The objective of this research was to characterize the enzymes involved in this reaction and to investigate the mechanism of the reaction. 2,2′,4′-Trichloroacetophenone was reduced to 2′,4′-dichloroacetophenone by glutathione-dependent cytosolic enzymes present in the liver, kidney, and brain. The actual substrate for the enzyme was S-(2,4-dichlorophenacyl)glutathione, which is formed by the nonenzymic reaction of 2,2′,4′-trichloroacetophenone and glutathione. The reaction mechanism may involve an enzyme-catalyzed nucleophilic attack of glutathione on the sulfur atom of S-(2,4-dichlorophenacyl)glutathione to yield a carbanion and glutathione disulfide; protonation of the carbanion would yield 2′,4′-dichloroacetophenone. Stoichiometry studies showed that the glutathione disulfide/2′,4′-dichloroacetophenone ratio was 1.25 ± 0.13.

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☆

This work was supported by National Institutes of Health Grant ES 01082. A preliminary report of this work was presented at the Fall Meeting of the American Society for Pharmacology and Experimental Therapeutics, Portland, OR, August 19–23 [Pharmacologist21, 215 (1979)].

†

Present address: Innertavle, S-90590 Umeå, Sweden.

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