Acetaminophen-induced liver injury is attenuated in male glutamate-cysteine ligase transgenic mice
| Autor: | Warren C. Ladiges, Michael J. Dabrowski, Nelson Fausto, Dianne Botta, Terrance J. Kavanagh, Sengkeo L. Srinouanprachanh, Charles L. White, Robert H. Pierce, Shengli Shi, Federico M. Farin, Carol B. Ware, Cassie L. Keener |
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| Rok vydání: | 2006 |
| Předmět: |
Male
acetaminophen overdose Transgene Glutamate-Cysteine Ligase Mice Transgenic Biology Biochemistry Antioxidants chemistry.chemical_compound Mice medicine Animals Ligase activity Transgenes Molecular Biology Acetaminophen chemistry.chemical_classification Liver injury Reactive oxygen species DNA ligase Models Genetic digestive oral and skin physiology Alanine Transaminase Cell Biology Glutathione medicine.disease Molecular biology Mice Inbred C57BL Mifepristone Oxidative Stress chemistry Liver medicine.drug |
| Zdroj: | The Journal of biological chemistry. 281(39) |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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