Deficiency of glutathione transferase Zeta causes oxidative stress and activation of antioxidant response pathways
dc.contributor.author | Blackburn, Anneke | |
dc.contributor.author | Matthaei, Klaus | |
dc.contributor.author | Lim, Cindy | |
dc.contributor.author | Taylor, Matthew | |
dc.contributor.author | Cappello, Jean | |
dc.contributor.author | Hayes, John D. | |
dc.contributor.author | Anders, Michael | |
dc.contributor.author | Board, Philip | |
dc.date.accessioned | 2015-12-13T23:00:55Z | |
dc.date.issued | 2006 | |
dc.date.updated | 2015-12-12T07:36:44Z | |
dc.description.abstract | 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. | |
dc.identifier.issn | 0026-895X | |
dc.identifier.uri | http://hdl.handle.net/1885/84350 | |
dc.publisher | American Society for Pharmacology and Experimental Therapeutics | |
dc.source | Molecular Pharmacology | |
dc.subject | Keywords: acetoacetic acid derivative; antioxidant; dichloroacetic acid; glutamate cysteine ligase; glutathione; glutathione transferase; glutathione transferase zeta; maleylacetoacetate; maleylacetone; paracetamol; phenylalanine; reduced nicotinamide adenine dinuc | |
dc.title | Deficiency of glutathione transferase Zeta causes oxidative stress and activation of antioxidant response pathways | |
dc.type | Journal article | |
local.bibliographicCitation.issue | 2 | |
local.bibliographicCitation.lastpage | 657 | |
local.bibliographicCitation.startpage | 650 | |
local.contributor.affiliation | Blackburn, Anneke, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Matthaei, Klaus, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Lim, Cindy, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Taylor, Matthew, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Cappello, Jean, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Hayes, John D., Ninewells Hospital | |
local.contributor.affiliation | Anders, Michael, University of Rochester | |
local.contributor.affiliation | Board, Philip, College of Medicine, Biology and Environment, ANU | |
local.contributor.authoremail | u4048450@anu.edu.au | |
local.contributor.authoruid | Blackburn, Anneke, u4048450 | |
local.contributor.authoruid | Matthaei, Klaus, u8200697 | |
local.contributor.authoruid | Lim, Cindy, u9902154 | |
local.contributor.authoruid | Taylor, Matthew, u9906948 | |
local.contributor.authoruid | Cappello, Jean, u9601131 | |
local.contributor.authoruid | Board, Philip, u7701651 | |
local.description.embargo | 2037-12-31 | |
local.description.notes | Imported from ARIES | |
local.description.refereed | Yes | |
local.identifier.absfor | 060104 - Cell Metabolism | |
local.identifier.ariespublication | MigratedxPub12631 | |
local.identifier.citationvolume | 69 | |
local.identifier.doi | 10.1124/mol.105.018911 | |
local.identifier.scopusID | 2-s2.0-31044456812 | |
local.identifier.uidSubmittedBy | Migrated | |
local.type.status | Published Version |
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