Acetaminophen-induced liver injury is attenuated in male glutamate-cysteine ligase transgenic mice.
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.
Botta
Dianne
D
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.
Shi
Shengli
S
White
Collin C
CC
Dabrowski
Michael J
MJ
Keener
Cassie L
CL
Srinouanprachanh
Sengkeo L
SL
Farin
Federico M
FM
Ware
Carol B
CB
Ladiges
Warren C
WC
Pierce
Robert H
RH
Fausto
Nelson
N
Kavanagh
Terrance J
TJ
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
D000975:Antioxidants; D015735:Mifepristone; D000082:Acetaminophen; D000410:Alanine Transaminase; D005721:Glutamate-Cysteine Ligase