Acetaminophen-induced liver injury is attenuated in male glutamate-cysteine ligase transgenic mice |
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Authors: | Botta Dianne Shi Shengli White Collin C Dabrowski Michael J Keener Cassie L Srinouanprachanh Sengkeo L Farin Federico M Ware Carol B Ladiges Warren C Pierce Robert H Fausto Nelson Kavanagh Terrance J |
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Affiliation: | Department of Environmental and Occupational Health Sciences, Comparative Medicine, and Pathology, and UW/NIEHS Center for Ecogenetics and Environmental Health, University of Washington, Seattle, Washington 68105, USA. |
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Abstract: | Acetaminophen overdose is a leading cause of drug-related acute liver failure in the United States. Glutathione, a tripeptide antioxidant protects cells against oxidative damage from reactive oxygen species and plays a crucial role in the detoxification of xenobiotics, including acetaminophen. Glutathione is synthesized in a two-step enzymatic reaction. Glutamate-cysteine ligase carries out the rate-limiting and first step in glutathione synthesis. We have generated C57Bl/6 mice that conditionally overexpress glutamate-cysteine ligase, and report here their resistance to acetaminophen-induced liver injury. Indices of liver injury included histopathology and serum alanine aminotransferase activity. Male transgenic mice induced to overexpress glutamate-cysteine ligase exhibited resistance to acetaminophen-induced liver injury when compared with acetaminophen-treated male mice carrying, but not expressing glutamate-cysteine ligase transgenes, or to female glutamate-cysteine ligase transgenic mice. We conclude that glutamate-cysteine ligase activity is an important factor in determining acetaminophen-induced liver injury in C57Bl/6 male mice. Because people are known to vary in their glutamate-cysteine ligase activity, this enzyme may also be an important determinant of sensitivity to acetaminophen-induced liver injury in humans. |
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