Mitochondrion is a novel site of biotransformation of dichloroacetate by glutathione transferase zeta

Abstract

Dichloroacetate (DCA) is an environmental contaminant as well as a potential therapeutic agent through its ability to stimulate the pyruvate dehydrogenase complex. Repeated doses of DCA result in reduced drug clearance, probably through inhibition of glutathione transferase zeta 1 (GSTz1), a cytosolic enzyme that converts DCA to glyoxylate. Because DCA is known to be taken up into mitochondria, its principal site of action, it is of interest to explore the role of mitochondria in DCA biotransformation. Incubation of human and rat liver mitochondria with 14C‐DCA resulted in biotransformation only when glutathione was added, and glyoxylate was identified as the major metabolite. Protein expression of GSTz was detected in human and rat liver mitochondria by Western Blotting against human GSTz1 antibody. In rats, the expression of GSTz per gram of liver is 14 times as much in cytosol as in mitochondria. Similar to cytosolic GSTz, the expression and activity of mitochondrial GSTz was markedly reduced in rats treated with 500 mg DCA/kg for 8 weeks. Studies of sub‐mitochondrial fractions of rat liver showed that GSTz is localized in the mitochondrial matrix. We conclude that the mitochondrion is a site of DCA biotransformation catalyzed by GSTz, an enzyme shown for the first time to be co‐localized in cytosol and mitochondrial matrix. Supported in part by the US Public Health Service, ES 07355, ES 014617, and 1UL1 RR029890.