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

alpha-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.