Deficiency of glutathione transferase Zeta causes oxidative stress and activation of antioxidant response pathways
Date
2006
Authors
Blackburn, Anneke
Matthaei, Klaus
Lim, Cindy
Taylor, Matthew
Cappello, Jean
Hayes, John D.
Anders, Michael
Board, Philip
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American Society for Pharmacology and Experimental Therapeutics
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.
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Keywords: acetoacetic acid derivative; antioxidant; dichloroacetic acid; glutamate cysteine ligase; glutathione; glutathione transferase; glutathione transferase zeta; maleylacetoacetate; maleylacetone; paracetamol; phenylalanine; reduced nicotinamide adenine dinuc
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Molecular Pharmacology
Type
Journal article
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2037-12-31
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