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.
Lim
Cindy E L
CE
John Curtin School of Medical Research, PO Box 334, Canberra ACT 2601, Australia.
Matthaei
Klaus I
KI
Blackburn
Anneke C
AC
Davis
Richard P
RP
Dahlstrom
Jane E
JE
Koina
Mark E
ME
Anders
M W
MW
Board
Philip G
PG
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