Inactivation of Glutathione Transferase Zeta by Dichloroacetic Acid and Other Fluorine-Lacking α-Haloalkanoic Acids

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Abstract
Dichloroacetic acid (DCA) is a contaminant of chlorinated drinking water supplies, is carcinogenic in rats and mice, and is a therapeutic agent used for the treatment of congenital lactic acidosis. The biotransformation of DCA to glyoxylic acid is catalyzed by glutathione transferase zeta (GSTZ). Treatment of rats and human subjects with DCA increases its plasma elimination half-life and reduces the extent of DCA biotransformation in rat hepatic cytosol. In the investigation presented here, the kinetics of the DCA-induced inactivation of GSTZ, the turnover of GSTZ, and the susceptibility of GSTZ to inactivation by a panel of α-haloacids were studied. DCA rapidly inactivated GSTZ in both rat hepatic cytosol and intact Fischer 344 rats. The time course of inactivation in vivo was mirrored by a concomitant loss of immunoreactive GSTZ protein. The turnover of GSTZ in rat liver was 0.21 day-1, which corresponded to a half-life of 3.3 days. The degree of GSTZ inactivation after daily administration of DCA could be predicted from the amount of inactivation after a single treatment. Other fluorine-lacking dihaloacetic acids also inactivated GSTZ, whereas α-monohaloacids and fluorine-containing dihaloacetic acids failed to inactivate GSTZ. These data show that the observed DCA-induced decrease in the level of DCA metabolism is caused by the inactivation of GSTZ.