title: Glutathione transferase zeta-catalyzed biotransformation of dichloroacetic acid and other alpha-haloacids.
abstract: 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 results showed that GSTZ catalyzed the oxygenation of bromochloro-, bromofluoro-, chlorofluoro-, dibromo-, and dichloroacetic acid, but not difluoroacetic acid, to glyoxylic acid. GSTZ also catalyzed the biotransformation of fluoroacetic acid to S-(carboxymethyl)glutathione, and of (R,S)-2-bromopropionic acid, (R)-, (S)-, and (R,S)-2-chloropropionic acid, and (R, S)-2-iodopropionic acid, but not (R,S)-2-fluoropropionic acid, to S-(alpha-methylcarboxymethyl)glutathione; and of 2, 2-dichloropropionic acid to pyruvate. No biotransformation of 3, 3-dichloropropionic acid was detected, and no GSTZ-catalyzed fluoride release from ethyl fluoroacetate and fluoroacetamide was observed. The relative rates of DCA biotransformation by hepatic cytosol were mouse > rat > human. Immunoblotting showed the presence of GSTZ in mouse, rat, and human liver cytosol. 13C NMR spectroscopic studies showed that [2-13C]glyoxylic acid was the only observable, stable metabolite of [2-13C]DCA. Also, glutathione was required, but was neither consumed nor oxidized to glutathione disulfide, during the oxygenation of DCA to glyoxylic acid. These results are consistent with a reaction mechanism that involves displacement of chloride from DCA by glutathione to afford S-(alpha-chlorocarboxymethyl)glutathione, which may undergo hydrolysis to give the hemithioacetal S-(alpha-hydroxycarboxymethyl)glutathione. Elimination of glutathione from the hemithioacetal would give glyoxylic acid.
authors.affiliation: Department of Pharmacology & Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 711, Rochester, New York 14642, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Tong
authors.forename: P G
authors.initials: PG
authors.lastname: Board
authors.forename: M W
authors.initials: MW
authors.lastname: Anders
mesh_terms: D000818:Animals; D001711:Biotransformation; D003600:Cytosol / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism*; D006016:Glycolates / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D051381:Rats; D013379:Substrate Specificity
chemical_list: D006016:Glycolates; D007527:Isoenzymes; D003999:Dichloroacetic Acid; D005982:Glutathione Transferase; D005978:Glutathione