ToxSci Advance Access originally published online on June 21, 2007
Toxicological Sciences 2007 99(2):628-636; doi:10.1093/toxsci/kfm165
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Glutamate Cysteine Ligase Modifier Subunit Deficiency and Gender as Determinants of Acetaminophen-Induced Hepatotoxicity in Mice
* Department of Environmental and Occupational Health Sciences
Department of Pathology
Department of Comparative Medicine, University of Washington, Seattle, Washington 98195
Schering-Plough Biopharma, Palo Alto, California 94304
2 To whom correspondence should be addressed at Department of Environmental and Occupational Health Sciences, Box 354695, University of Washington, Seattle, WA 98195. Fax: (206) 685-4696. E-mail: tjkav{at}u.washington.edu.
Received June 8, 2007; accepted June 12, 2007
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Abstract |
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The analgesic and antipyretic drug acetaminophen (APAP) is bioactivated to the reactive intermediate N-acetyl-p-benzoquinoneimine, which is scavenged by glutathione (GSH). APAP overdose can deplete GSH leading to the accumulation of APAP–protein adducts and centrilobular necrosis in the liver. N-acetylcysteine (NAC), a cysteine prodrug and GSH precursor, is often given as a treatment for APAP overdose. The rate-limiting step in GSH biosynthesis is catalyzed by glutamate cysteine ligase (GCL) a heterodimer composed of catalytic and modifier (GCLM) subunits. Previous studies have indicated that GCL activity is likely to be an important determinant of APAP toxicity. In this study, we investigated APAP toxicity, and NAC or GSH ethyl ester (GSHee)–mediated rescue in mice with normal or compromised GCLM expression. Gclm wild-type, heterozygous, and null mice were administered APAP (500 mg/kg) alone, or immediately following NAC (800 mg/kg) or GSHee (168 mg/kg), and assessed for hepatotoxicity 6 h later. APAP caused GSH depletion in all mice. Gclm null and heterozygous mice exhibited more extensive hepatic damage compared to wild-type mice as assessed by serum alanine aminotransferase activity and histopathology. Additionally, male Gclm wild-type mice demonstrated greater APAP-induced hepatotoxicity than female wild-type mice. Cotreatment with either NAC or GSHee mitigated the effects of APAP in Gclm wild-type and heterozygous mice, but not in Gclm null mice. Collectively, these data reassert the importance of GSH in protection against APAP-induced hepatotoxicity, and indicate critical roles for GCL activity and gender in APAP-induced liver damage in mice.
Key Words: glutathione deficiency; acetaminophen; gender differences; transgenic mice.
1 L.A.M. and I.M. contributed equally in the preparation of this manuscript.
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