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

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 t...

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Autores principales: Mohar, Isaac, Stamper, Brendan D., Rademacher, Peter M., White, Collin C., Nelson, Sidney D., Kavanagh, Terrance J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926121/
https://www.ncbi.nlm.nih.gov/pubmed/24563856
http://dx.doi.org/10.1016/j.redox.2014.01.008
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author Mohar, Isaac
Stamper, Brendan D.
Rademacher, Peter M.
White, Collin C.
Nelson, Sidney D.
Kavanagh, Terrance J.
author_facet Mohar, Isaac
Stamper, Brendan D.
Rademacher, Peter M.
White, Collin C.
Nelson, Sidney D.
Kavanagh, Terrance J.
author_sort Mohar, Isaac
collection PubMed
description 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.
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spelling pubmed-39261212014-02-21 Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6 Mohar, Isaac Stamper, Brendan D. Rademacher, Peter M. White, Collin C. Nelson, Sidney D. Kavanagh, Terrance J. Redox Biol Research Paper 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. Elsevier 2014-01-20 /pmc/articles/PMC3926121/ /pubmed/24563856 http://dx.doi.org/10.1016/j.redox.2014.01.008 Text en © 2014 The Authors https://creativecommons.org/licenses/by-nc-nd/3.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License (https://creativecommons.org/licenses/by-nc-nd/3.0/) .
spellingShingle Research Paper
Mohar, Isaac
Stamper, Brendan D.
Rademacher, Peter M.
White, Collin C.
Nelson, Sidney D.
Kavanagh, Terrance J.
Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6
title Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6
title_full Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6
title_fullStr Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6
title_full_unstemmed Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6
title_short Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6
title_sort acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926121/
https://www.ncbi.nlm.nih.gov/pubmed/24563856
http://dx.doi.org/10.1016/j.redox.2014.01.008
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