Stereospecific Toxicokinetics of Bromochloro- and Chlorofluoroacetate: Effect of GST-ζ Depletion

Abstract

The chloro- and bromohaloacetates are drinking water disinfection by-products and rodent carcinogens. Chloro—bromo dihaloacetates are also mechanism-based inhibitors of glutathione S-transferase-ζ (GSTZ1–1). We studied the stereospecific toxicokinetics and in vitro metabolism of two chiral dihaloacetates in male F344 rats: (−),(+)-bromochloroacetate (BCA) and racemic chlorofluoroacetate (CFA), a non-GST-ζ-inhibiting dihaloacetate. These experiments were repeated in animals that had previously been treated with dichloroacetate (DCA) to deplete GST-ζ activity. Results indicated that the elimination half-life of (−)-BCA was 0.07 compared to 0.40 h for (+)-BCA in naive rats. A comparable difference in elimination half-life was also observed for the CFA stereoisomers (0.79 vs 0.11 h). In GST-ζ-depleted rats, stereospecific elimination of (−),(+)-BCA was absent, with both stereoisomers having an elimination half-life of approximately 0.4 h. This finding was in contrast to results for CFA, which still maintained the same relative difference in elimination rate between its stereoisomers, although overall elimination was diminished in GST-ζ-depleted rats. Results of in vitro metabolism experiments indicated (−)-BCA was affected by modulating GST-ζ activity, with the intrinsic metabolic clearance decreasing from 2.81 to 0.15 ml h−1 mg·protein−1 (naive, GST-ζ depleted) compared with values for (+)-BCA (0.30 and 0.31 ml h−1 mg·protein−1). Incubations with 350 μM diethyldithiocarbamate preferentially decreased (+)-BCA metabolism in naive and GST-ζ-depleted cytosol. These results indicate (+)-BCA is a poor substrate for GST-ζ and its metabolism is controlled by an additional GST isoenzyme.