Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases

Am J Pathol. 2004 Aug;165(2):679-93. doi: 10.1016/S0002-9440(10)63332-9.

Abstract

Glutathione transferase zeta (GSTZ1-1) is the major enzyme that catalyzes the metabolism of alpha-halo acids such as dichloroacetic acid, a carcinogenic contaminant of chlorinated water. GSTZ1-1 is identical with maleylacetoacetate isomerase, which catalyzes the penultimate step in the catabolic pathways for phenylalanine and tyrosine. In this study we have deleted the Gstz1 gene in BALB/c mice and characterized their phenotype. Gstz1(-/-) mice do not have demonstrable activity with maleylacetone and alpha-halo acid substrates, and other GSTs do not compensate for the loss of this enzyme. When fed a standard diet, the GSTZ1-1-deficient mice showed enlarged liver and kidneys as well as splenic atrophy. Light and electron microscopic examination revealed multifocal hepatitis and ultrastructural changes in the kidney. The addition of 3% (w/v) phenylalanine to the drinking water was lethal for young mice (<28 days old) and caused liver necrosis, macrovesicular steatosis, splenic atrophy, and a significant loss of circulating leukocytes in older surviving mice. GSTZ1-1-deficient mice showed constitutive induction of alpha, mu, and pi class GSTs as well as NAD(P)H:quinone oxidoreductase 1. The overall response is consistent with the chronic accumulation of a toxic metabolite(s). We detected the accumulation of succinylacetone in the serum of deficient mice but cannot exclude the possibility that maleylacetoacetate and maleylacetone may also accumulate.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetone / analogs & derivatives*
  • Acetone / metabolism
  • Animals
  • Diet
  • Female
  • Glutathione S-Transferase pi
  • Glutathione Transferase / deficiency
  • Glutathione Transferase / metabolism*
  • Glutathione Transferase / physiology*
  • Hepatitis / etiology
  • Heptanoates / metabolism
  • Isoenzymes / metabolism*
  • Kidney / enzymology
  • Kidney / pathology*
  • Leukocytes / metabolism
  • Liver / enzymology
  • Liver / pathology*
  • Male
  • Maleates / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • Phenylalanine / administration & dosage
  • Spleen / enzymology
  • Spleen / pathology
  • Up-Regulation
  • cis-trans-Isomerases / metabolism*

Substances

  • Heptanoates
  • Isoenzymes
  • Maleates
  • maleylacetone
  • Acetone
  • Phenylalanine
  • succinylacetone
  • NAD(P)H Dehydrogenase (Quinone)
  • Gstz1 protein, mouse
  • Glutathione S-Transferase pi
  • Glutathione Transferase
  • glutathione S-transferase alpha
  • cis-trans-Isomerases
  • maleylacetoacetate isomerase