Modulating GSH Synthesis Using Glutamate Cysteine Ligase Transgenic and Gene-Targeted Mice

Dianne Botta Department of Environmental and Occupational Health Sciences, University of Washington, SeattleUSA

Collin C. White Department of Environmental and Occupational Health Sciences, University of Washington, SeattleUSA

Portia Vliet-Gregg Department of Environmental and Occupational Health Sciences, University of Washington, SeattleUSA

Isaac Mohar Department of Environmental and Occupational Health Sciences, University of Washington, SeattleUSA

Shengli Shi Department of Environmental and Occupational Health Sciences, University of Washington, SeattleUSA

Monica B. McGrath Department of Environmental and Occupational Health Sciences, University of Washington, SeattleUSA

Lisa A. McConnachie Department of Environmental and Occupational Health Sciences, University of Washington, SeattleUSA

Terrance J. Kavanagh Department of Environmental and Occupational Health Sciences, University of Washington, SeattleUSA

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Abstract

Glutathione (GSH) is an important antioxidant and cofactor for glutathione S-transferase conjugation. GSH synthesis is catalyzed by glutamate cysteine ligase (GCL), composed of catalytic (GCLC) and modifier (GCLM) subunits. Transgenic mice that conditionally over express GCL subunits are protected from acetaminophen induced liver injury. Gclm null mice exhibit low GSH levels and enhanced sensitivity to acetaminophen. When Gclm expression and GCL activity are restored in Gclm conditional transgenic X Gclm null mice, they become resistant to APAP-induced liver damage. These animal models are a valuable resource for investigating the role of GSH synthesis in modulating oxidative damage and drug-induced hepatotoxicity.

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Acknowledgments

We wish to express our thanks to Mr. Kyle Samek for technical assistance. This work was supported by NIH grants U19ES11378, P42ES04696, R01ES10849, T32ES07032 and P30ES07033.

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Modulating GSH Synthesis Using Glutamate Cysteine Ligase Transgenic and Gene-Targeted Mice

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