title: Acetaminophen-induced liver injury is attenuated in male glutamate-cysteine ligase transgenic mice.
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.
authors.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.
authors.forename: Dianne
authors.initials: D
authors.lastname: Botta
authors.forename: Shengli
authors.initials: S
authors.lastname: Shi
authors.forename: Collin C
authors.initials: CC
authors.lastname: White
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dabrowski
authors.forename: Cassie L
authors.initials: CL
authors.lastname: Keener
authors.forename: Sengkeo L
authors.initials: SL
authors.lastname: Srinouanprachanh
authors.forename: Federico M
authors.initials: FM
authors.lastname: Farin
authors.forename: Carol B
authors.initials: CB
authors.lastname: Ware
authors.forename: Warren C
authors.initials: WC
authors.lastname: Ladiges
authors.forename: Robert H
authors.initials: RH
authors.lastname: Pierce
authors.forename: Nelson
authors.initials: N
authors.lastname: Fausto
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000293:injuries*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015735:Mifepristone / Q000494:pharmacology; D008957:Models, Genetic; D018384:Oxidative Stress; D019076:Transgenes
chemical_list: D000975:Antioxidants; D015735:Mifepristone; D000082:Acetaminophen; D000410:Alanine Transaminase; D005721:Glutamate-Cysteine Ligase