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Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase.

Publication ,  Journal Article
Du, K; Williams, CD; McGill, MR; Jaeschke, H
Published in: Toxicol Appl Pharmacol
November 15, 2014

UNLABELLED: Acetaminophen (APAP) overdose causes severe hepatotoxicity in animals and humans. However, the mechanisms underlying the gender differences in susceptibility to APAP overdose in mice have not been clarified. In our study, APAP (300mg/kg) caused severe liver injury in male mice but 69-77% lower injury in females. No gender difference in metabolic activation of APAP was found. Hepatic glutathione (GSH) was rapidly depleted in both genders, while GSH recovery in female mice was 2.6 fold higher in the mitochondria at 4h, and 2.5 and 3.3 fold higher in the total liver at 4h and 6h, respectively. This faster recovery of GSH, which correlated with greater induction of glutamate-cysteine ligase, attenuated mitochondrial oxidative stress in female mice, as suggested by a lower GSSG/GSH ratio at 6h (3.8% in males vs. 1.4% in females) and minimal centrilobular nitrotyrosine staining. While c-jun N-terminal kinase (JNK) activation was similar at 2 and 4h post-APAP, it was 3.1 fold lower at 6h in female mice. However, female mice were still protected by the JNK inhibitor SP600125. 17β-Estradiol pretreatment moderately decreased liver injury and oxidative stress in male mice without affecting GSH recovery. CONCLUSION: The lower susceptibility of female mice is achieved by the improved detoxification of reactive oxygen due to accelerated recovery of mitochondrial GSH levels, which attenuates late JNK activation and liver injury. However, even the reduced injury in female mice was still dependent on JNK. While 17β-estradiol partially protects male mice, it does not affect hepatic GSH recovery.

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Published In

Toxicol Appl Pharmacol

DOI

EISSN

1096-0333

Publication Date

November 15, 2014

Volume

281

Issue

1

Start / End Page

58 / 66

Location

United States

Related Subject Headings

  • Toxicology
  • Sex Characteristics
  • Oxidative Stress
  • Mitochondria, Liver
  • Mice, Inbred C57BL
  • Mice
  • Male
  • JNK Mitogen-Activated Protein Kinases
  • Glutathione
  • Female
 

Citation

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Du, K., Williams, C. D., McGill, M. R., & Jaeschke, H. (2014). Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase. Toxicol Appl Pharmacol, 281(1), 58–66. https://doi.org/10.1016/j.taap.2014.09.002
Du, Kuo, C David Williams, Mitchell R. McGill, and Hartmut Jaeschke. “Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase.Toxicol Appl Pharmacol 281, no. 1 (November 15, 2014): 58–66. https://doi.org/10.1016/j.taap.2014.09.002.
Du, Kuo, et al. “Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase.Toxicol Appl Pharmacol, vol. 281, no. 1, Nov. 2014, pp. 58–66. Pubmed, doi:10.1016/j.taap.2014.09.002.
Journal cover image

Published In

Toxicol Appl Pharmacol

DOI

EISSN

1096-0333

Publication Date

November 15, 2014

Volume

281

Issue

1

Start / End Page

58 / 66

Location

United States

Related Subject Headings

  • Toxicology
  • Sex Characteristics
  • Oxidative Stress
  • Mitochondria, Liver
  • Mice, Inbred C57BL
  • Mice
  • Male
  • JNK Mitogen-Activated Protein Kinases
  • Glutathione
  • Female