title: Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6.
abstract: 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.
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Box 354695, Seattle, WA 98195, USA.
authors.forename: Isaac
authors.initials: I
authors.lastname: Mohar
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Stamper
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Rademacher
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Box 354695, Seattle, WA 98195, USA.
authors.forename: Collin C
authors.initials: CC
authors.lastname: White
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA.
authors.forename: Sidney D
authors.initials: SD
authors.lastname: Nelson
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Box 354695, Seattle, WA 98195, USA.
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology*; D004351:Drug Resistance; D005260:Female; D055786:Gene Knockout Techniques; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D005978:Glutathione / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D054465:Peroxiredoxin VI / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D000082:Acetaminophen; D054465:Peroxiredoxin VI; C515983:Prdx6 protein, mouse; D000410:Alanine Transaminase; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: Acetaminophen; Gclm; Gender; Glutathione; Mitochondria; Peroxiredoxin-6