Deficiency of glutathione transferase zeta causes oxidative stress and activation of antioxidant response pathways.
Glutathione S-transferase (GST) zeta (GSTZ1-1) plays a significant role in the catabolism of phenylalanine and tyrosine, and a deficiency of GSTZ1-1 results in the accumulation of maleylacetoacetate and its derivatives maleylacetone (MA) and succinylacetone. Induction of GST subunits was detected in the liver of Gstz1(-/-) mice by Western blotting with specific antisera and high-performance liquid chromatography analysis of glutathione affinity column-purified proteins. The greatest induction was observed in members of the mu class. Induction of NAD(P)H:quinone oxidoreductase 1 and the catalytic and modifier subunits of glutamate-cysteine ligase was also observed. Many of the enzymes that are induced in Gstz1(-/-) mice are regulated by antioxidant response elements that respond to oxidative stress via the Keap1/Nrf2 pathway. It is significant that diminished glutathione concentrations were also observed in the liver of Gstz1(-/-) mice, which supports the conclusion that under normal dietary conditions, the accumulation of electrophilic intermediates such as maleylacetoacetate and MA results in a high level of oxidative stress. Elevated GST activities in the livers of Gstz1(-/-) mice suggest that GSTZ1-1 deficiency may alter the metabolism of some drugs and xenobiotics. Gstz1(-/-) mice given acetaminophen demonstrated increased hepatotoxicity compared with wild-type mice. This toxicity may be attributed to the increased GST activity or the decreased hepatic concentrations of glutathione, or both. Patients with acquired deficiency of GSTZ1-1 caused by therapeutic exposure to dichloroacetic acid for the clinical treatment of lactic acidosis may be at increased risk of drug- and chemical-induced toxicity.
Blackburn
Anneke C
AC
Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra.
Matthaei
Klaus I
KI
Lim
Cindy
C
Taylor
Matthew C
MC
Cappello
Jean Y
JY
Hayes
John D
JD
Anders
M W
MW
Board
Philip G
PG
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000172:deficiency* / Q000235:genetics; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000235:genetics*; D015262:Xenobiotics / Q000378:metabolism
D000975:Antioxidants; D007527:Isoenzymes; D015262:Xenobiotics; D000082:Acetaminophen; C498694:Gstz1 protein, mouse; D005982:Glutathione Transferase; D005978:Glutathione