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J. Biol. Chem., Vol. 281, Issue 39, 28865-28875, September 29, 2006

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Acetaminophen-induced Liver Injury Is Attenuated in Male Glutamate-cysteine Ligase Transgenic Mice^*

Dianne Botta, Shengli Shi¹, Collin C. White, Michael J. Dabrowski, Cassie L. Keener, Sengkeo L. Srinouanprachanh, Federico M. Farin, Carol B. Ware, Warren C. Ladiges, Robert H. Pierce^¶, Nelson Fausto^||, and Terrance J. Kavanagh²

From the Departments 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 and the ^¶Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

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.

Received for publication, May 30, 2006 , and in revised form, July 12, 2006.

^* This work was supported by National Institutes of Health Grants 5R01ES010849, 5P01AG001751, 5P42ES004696, and 2P30ES007033. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: Dept. of Pathology and Laboratory of Medicine, University of California, Los Angeles, CA 90095.

² To whom correspondence should be addressed: Box 354695, University of Washington, Seattle, WA 98195. Tel.: 206-685-8479; Fax: 206-685-4696; E-mail: tjkav{at}u.washington.edu.

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