Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6

Redox Biology. 2014;2(C):377-387 DOI 10.1016/j.redox.2014.01.008

 

Journal Homepage

Journal Title: Redox Biology

ISSN: 2213-2317 (Online)

Publisher: Elsevier

Society/Institution: Society for Free Radical Biology and Medicine; Society for Free Radical Research-Europe

LCC Subject Category: Medicine: Medicine (General) | Science: Biology (General)

Country of publisher: Netherlands

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS

Isaac Mohar (Department of Environmental and Occupational Health Sciences, University of Washington, Box 354695, Seattle, WA 98195, USA)
Brendan D. Stamper (Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA)
Peter M. Rademacher (Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA)
Collin C. White (Department of Environmental and Occupational Health Sciences, University of Washington, Box 354695, Seattle, WA 98195, USA)
Sidney D. Nelson (Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA)
Terrance J. Kavanagh (Department of Environmental and Occupational Health Sciences, University of Washington, Box 354695, Seattle, WA 98195, USA)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 10 weeks

 

Abstract | Full Text

The mechanism by which acetaminophen (APAP) causes liver damage evokes many aspects drug metabolism, oxidative chemistry, and genetic-predisposition. In this study, we leverage the relative resistance of female C57BL/6 mice to APAP-induced liver damage (AILD) compared to male C57BL/6 mice in order to identify the cause(s) of sensitivity. Furthermore, we use mice that are either heterozygous (HZ) or null (KO) for glutamate cysteine ligase modifier subunit (Gclm), in order to titrate the toxicity relative to wild-type (WT) mice. Gclm is important for efficient de novo synthesis of glutathione (GSH). APAP (300 mg/kg, ip) or saline was administered and mice were collected at 0, 0.5, 1, 2, 6, 12, and 24 h. Male mice showed marked elevation in serum alanine aminotransferase by 6 h. In contrast, female WT and HZ mice showed minimal toxicity at all time points. Female KO mice, however, showed AILD comparable to male mice. Genotype-matched male and female mice showed comparable APAP–protein adducts, with Gclm KO mice sustaining significantly greater adducts. ATP was depleted in mice showing toxicity, suggesting impaired mitochondria function. Indeed, peroxiredoxin-6, a GSH-dependent peroxiredoxin, was preferentially adducted by APAP in mitochondria of male mice but rarely adducted in female mice. These results support parallel mechanisms of toxicity where APAP adduction of peroxiredoxin-6 and sustained GSH depletion results in the collapse of mitochondria function and hepatocyte death. We conclude that adduction of peroxiredoxin-6 sensitizes male C57BL/6 mice to toxicity by acetaminophen.