Perturbation of maleylacetoacetic acid metabolism in rats with dichloroacetic Acid-induced glutathione transferase zeta deficiency

Toxicol Sci. 2003 Jul;74(1):192-202. doi: 10.1093/toxsci/kfg104. Epub 2003 May 2.

Abstract

Glutathione transferase zeta (GSTZ1-1) catalyzes the isomerization of maleylacetoacetate (MAA) to fumarylacetoacetate, the penultimate step in the tyrosine degradation pathway. GSTZ1-1 is inactivated by dichloroacetic acid (DCA), which is used for the clinical management of congenital lactic acidosis and is a drinking-water contaminant. Metabolic changes associated with chemically induced GSTZ1-1 deficiency are poorly understood. The objective of this study was to investigate 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. Urine from DCA-treated rats inhibited delta-aminolevulinic acid dehydratase (delta-ALAD) activity, which is used for the diagnosis of hereditary tyrosinemia type I. Mass spectrometric analyses of urine from rats given DCA demonstrated elevated excretion of MAA and its decarboxylation product, maleylacetone (MA); succinylacetone (SA), the reduced analogue of MA, was not detected. DCA-induced changes in MA excretion were dose-dependent and were significantly elevated after day 2 of treatment. MA excretion was reversible after discontinuation of DCA treatment and was enhanced 10-fold by the coadministration of homogentisic acid (HGA). MA was cytotoxic to hepatocytes in vitro (EC50 ~ 350 microM) but morphological changes were not observed in liver, kidney, and brain of rats given both DCA and HGA. These data indicate that DCA-induced inactivation of GSTZ1-1 leads to formation of an MAA-derived intermediate, MA, that may be a mediator and biomarker for DCA-associated toxicities.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cell Survival
  • Chromatography, Liquid
  • Dichloroacetic Acid / pharmacology*
  • Dichloroacetic Acid / urine
  • Gas Chromatography-Mass Spectrometry
  • Glutathione Transferase / deficiency*
  • Kinetics
  • Liver / pathology
  • Male
  • Maleates / metabolism*
  • Maleates / urine
  • Mice
  • Mice, Transgenic
  • Porphobilinogen Synthase / metabolism
  • Rats
  • Rats, Inbred F344
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Tyrosine / metabolism

Substances

  • Maleates
  • Tumor Necrosis Factor-alpha
  • maleoylacetic acid
  • Tyrosine
  • Dichloroacetic Acid
  • Gstz1 protein, mouse
  • Gstz1 protein, rat
  • Glutathione Transferase
  • Porphobilinogen Synthase