Inactivation of glutathione transferase zeta by dichloroacetic acid and other fluorine-lacking alpha-haloalkanoic acids

Dichloroacetic acid (DCA) is a contaminant of chlorinated drinking water su pplies, is carcinogenic in rats and mice, and is a therapeutic agent used f or the treatment of congenital lactic acidosis. The biotransformation of DC A to glyoxylic acid is catalyzed by glutathione transferase zeta (GSTZ). Tr eatment of rats and human subjects with DCA increases its plasma eliminatio n half-life and reduces the extent of DCA biotransformation in rat hepatic cytosol. In the investigation presented here, the kinetics of the DCA-induc ed inactivation of GSTZ, the turnover of GSTZ, and the susceptibility of GS TZ to inactivation by a panel of alpha-haloacids were studied. DCA rapidly inactivated GSTZ in both rat hepatic cytosol and intact Fischer 344 rats. T he time course of inactivation in vivo was mirrored by a concomitant loss o f immunoreactive GSTZ protein. The turnover of GSTZ in rat liver was 0.21 d ay-1, which corresponded to a half-life of 3.3 days. The degree of GSTZ ina ctivation after daily administration of DCA could be predicted from the amo unt of inactivation after a single treatment. Other fluorine-lacking dihalo acetic acids also inactivated GSTZ, whereas alpha-monohaloacids and fluorin e-containing dihaloacetic acids failed to inactivate GSTZ. These data show that the observed DCA-induced decrease in the level of DCA metabolism is ca used by the inactivation of GSTZ.