Deficiency of glutathione transferase Zeta causes oxidative stress and activation of antioxidant response pathways

dc.contributor.authorBlackburn, Anneke
dc.contributor.authorMatthaei, Klaus
dc.contributor.authorLim, Cindy
dc.contributor.authorTaylor, Matthew
dc.contributor.authorCappello, Jean
dc.contributor.authorHayes, John D.
dc.contributor.authorAnders, Michael
dc.contributor.authorBoard, Philip
dc.date.accessioned2015-12-13T23:00:55Z
dc.date.issued2006
dc.date.updated2015-12-12T07:36:44Z
dc.description.abstractGlutathione 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.
dc.identifier.issn0026-895X
dc.identifier.urihttp://hdl.handle.net/1885/84350
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics
dc.sourceMolecular Pharmacology
dc.subjectKeywords: acetoacetic acid derivative; antioxidant; dichloroacetic acid; glutamate cysteine ligase; glutathione; glutathione transferase; glutathione transferase zeta; maleylacetoacetate; maleylacetone; paracetamol; phenylalanine; reduced nicotinamide adenine dinuc
dc.titleDeficiency of glutathione transferase Zeta causes oxidative stress and activation of antioxidant response pathways
dc.typeJournal article
local.bibliographicCitation.issue2
local.bibliographicCitation.lastpage657
local.bibliographicCitation.startpage650
local.contributor.affiliationBlackburn, Anneke, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationMatthaei, Klaus, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLim, Cindy, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationTaylor, Matthew, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationCappello, Jean, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationHayes, John D., Ninewells Hospital
local.contributor.affiliationAnders, Michael, University of Rochester
local.contributor.affiliationBoard, Philip, College of Medicine, Biology and Environment, ANU
local.contributor.authoremailu4048450@anu.edu.au
local.contributor.authoruidBlackburn, Anneke, u4048450
local.contributor.authoruidMatthaei, Klaus, u8200697
local.contributor.authoruidLim, Cindy, u9902154
local.contributor.authoruidTaylor, Matthew, u9906948
local.contributor.authoruidCappello, Jean, u9601131
local.contributor.authoruidBoard, Philip, u7701651
local.description.embargo2037-12-31
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.absfor060104 - Cell Metabolism
local.identifier.ariespublicationMigratedxPub12631
local.identifier.citationvolume69
local.identifier.doi10.1124/mol.105.018911
local.identifier.scopusID2-s2.0-31044456812
local.identifier.uidSubmittedByMigrated
local.type.statusPublished Version

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