Stereospecific toxicokinetics of bromochloro- and chlorofluoroacetate: effect of GST-zeta depletion.
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-zeta (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-zeta-inhibiting dihaloacetate. These experiments were repeated in animals that had previously been treated with dichloroacetate (DCA) to deplete GST-zeta 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-zeta-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-zeta-depleted rats. Results of in vitro metabolism experiments indicated (-)-BCA was affected by modulating GST-zeta activity, with the intrinsic metabolic clearance decreasing from 2.81 to 0.15 ml h(-1) mg.protein(-1) (naive, GST-zeta depleted) compared with values for (+)-BCA (0.30 and 0.31 ml h(-1) mg.protein(-1)). Incubations with 350 microM diethyldithiocarbamate preferentially decreased (+)-BCA metabolism in naive and GST-zeta-depleted cytosol. These results indicate (+)-BCA is a poor substrate for GST-zeta and its metabolism is controlled by an additional GST isoenzyme.
Schultz
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Molecular Biosciences Department, Battelle Pacific Northwest Division, Richland, Washington 99352, USA.
Sylvester
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D000085:Acetates / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D000818:Animals; D019540:Area Under Curve; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism
D000085:Acetates; C120963:chlorofluoroacetic acid; C099813:bromochloroacetic acid; C498692:Gstz1 protein, rat; D005982:Glutathione Transferase