Glutathione transferase zeta-catalyzed biotransformation of dichloroacetic acid and other alpha-haloacids.

  title={Glutathione transferase zeta-catalyzed biotransformation of dichloroacetic acid and other alpha-haloacids.},
  author={Zeen Tong and Philip G Board and M W Anders},
  journal={Chemical research in toxicology},
  volume={11 11},
Dichloroacetic acid (DCA) is a common drinking-water contaminant, is hepatocarcinogenic in rats and mice, and is a therapeutic agent used clinically in the management of lactic acidosis. Recent studies show that glutathione transferase Zeta (GSTZ) catalyzes the oxygenation of DCA to glyoxylic acid [Tong et al. (1998) Biochem. J. 331, 371-374]. In the present studies, the substrate selectivity of GSTZ, the kinetics of DCA metabolism, and the fate of DCA and glutathione were investigated. The… 
Glutathione transferase zeta-catalyzed biotransformation of deuterated dihaloacetic acids.
The data afford an explanation of the failure of fluorine-containing dihaloacetic acids to inactivate GSTZ: dichloroacetic acid is converted to glyoxylic acid and inactivates GSTZ, whereas chlorofluoroacetic Acid is biotransformed to gly Oxylic acid, but produces negligible inactivation.
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
Perturbation of maleylacetoacetic acid metabolism in rats with dichloroacetic Acid-induced glutathione transferase zeta deficiency.
Investigation of the biochemical and toxicological effects of giving 0.3-1.2 mmol DCA/kg/day for 5 days on MAA-metabolism in male Fischer rats indicates that DCA-induced inactivation of GSTZ1-1 leads to formation of an M AA-derived intermediate, MA, that may be a mediator and biomarker for DC a-associated toxicities.
Toxicokinetics and oral bioavailability of halogenated acetic acids mixtures in naïve and GSTzeta-depleted rats.
  • S. Saghir, I. Schultz
  • Biology
    Toxicological sciences : an official journal of the Society of Toxicology
  • 2005
In both mixtures, GSTzeta depletion primarily affected the toxicokinetics of di-HAAs (DCAA, BCAA, and DBAA), with the total body clearance (Cl b) decreasing 3- to 10-fold.
Mitochondrion as a Novel Site of Dichloroacetate Biotransformation by Glutathione Transferase ζ1
It is concluded that the mitochondrion is a novel site of DCA biotransformation catalyzed by GSTZ1, an enzyme colocalized in cytosol and mitochondrial matrix.
Inhibition of glutathione S-transferase zeta and tyrosine metabolism by dichloroacetate: a potential unifying mechanism for its altered biotransformation and toxicity.
It is indicated that humans or rodents exposed to DCA may accumulate MA and/or MAA which inhibit(s) GSTz and, consequently, DCA biotransformation and DCA-induced inhibition of tyrosine catabolism may account for the toxicity of this xenobiotic in humans and other species.
Nephrotoxicity of chlorofluoroacetic acid in rats.
The nephrotoxicity of CFA was associated with a dose-dependent increase in inorganic fluoride excretion, and Electron microscopic analysis indicated a role for apoptosis in CFA-induced cell death.
Haloacetic Acid Water Disinfection Byproducts Affect Pyruvate Dehydrogenase Activity and Disrupt Cellular Metabolism.
The primary finding of this work is that mono- versus multi-HAAs address different molecular targets, and the results are generally consistent with a model in which monoHAAs activate the PDC through GAPDH inhibition-mediated disruption in cellular metabolites, including altering ATP-to-ADP and NADH- to-NAD ratios.