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.
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.
John Curtin School of Medical Research, PO Box 334, Canberra ACT 2601, Australia.
Cindy E L
CE
Lim
Klaus I
KI
Matthaei
Anneke C
AC
Blackburn
Richard P
RP
Davis
Jane E
JE
Dahlstrom
Mark E
ME
Koina
M W
MW
Anders
Philip G
PG
Board
D000096:Acetone / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D004032:Diet; D005260:Female; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology*; D006505:Hepatitis / Q000209:etiology; D006537:Heptanoates / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology / Q000473:pathology*; D007962:Leukocytes / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology*; D008297:Male; D008298:Maleates / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D010649:Phenylalanine / Q000008:administration & dosage; D013154:Spleen / Q000201:enzymology / Q000473:pathology; D015854:Up-Regulation; D019745:cis-trans-Isomerases / Q000378:metabolism*
D006537:Heptanoates; D007527:Isoenzymes; D008298:Maleates; C460372:maleylacetone; D000096:Acetone; D010649:Phenylalanine; C020804:succinylacetone; D016660:NAD(P)H Dehydrogenase (Quinone); C498694:Gstz1 protein, mouse; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D019745:cis-trans-Isomerases; C021531:maleylacetoacetate isomerase