Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Molecular Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1107-3756 Online ISSN: 1791-244X
Journal Cover
September-2017 Volume 40 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
September-2017 Volume 40 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Glutathione peroxidase 3 is a protective factor against acetaminophen‑induced hepatotoxicity in vivo and in vitro

  • Authors:
    • Syu-Ichi Kanno
    • Ayako Tomizawa
    • Shin Yomogida
    • Akiyoshi Hara
  • View Affiliations / Copyright

    Affiliations: Department of Clinical Pharmacotherapeutics, Tohoku Medical and Pharmaceutical University, Aoba‑ku, Sendai 981‑8558, Japan
    Copyright: © Kanno et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 748-754
    |
    Published online on: July 3, 2017
       https://doi.org/10.3892/ijmm.2017.3049
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Acetaminophen (APAP) is a widely available antipyretic and analgesic; however, overdose of the drug inflicts severe damage to the liver. It is well established that the hepatotoxicity of APAP is initiated by formation of a reactive metabolite, N‑acetyl‑p‑benzoquinone imine (NAPQI), which can be detoxified by conjugation with reduced glutathione (GSH), a typical antioxidant. We recently found that the blood mRNA expression level of glutathione peroxidase 3 (Gpx3), which catalyzes the oxidation of GSH, is associated with the extent of APAP‑induced hepatotoxicity in mice. The present study was carried out to determine the in vivo and in vitro role of GPx3 in APAP‑induced hepatotoxicity. In in vivo experiments, oral administration of APAP to mice induced liver injury. Such liver injury was greater in males than in females, although no gender difference in the plasma concentration of APAP was found. Female mice had a 2‑fold higher expression of Gpx3 mRNA and higher plasma GPx activity than male mice. 17β‑estradiol, a major female hormone, decreased APAP‑induced hepatotoxicity and increased both the expression of blood Gpx3 mRNA and plasma GPx activity, suggesting that the cytoprotective action of this hormone is mediated by the increase in GPx3. To further clarify the role of GPx3 in APAP‑induced hepatotoxicity, we evaluated the effect of a change in cellular GPx3 expression resulting from transfection of either siRNA‑GPx3 or a GPx3 expression vector on NAPQI‑induced cellular injury (as assessed by a tetrazolium assay) in in vitro experiments using heterogeneous cultured human cell lines (Huh‑7 or K562). NAPQI‑induced cell death was reduced by increased GPx3 and was enhanced by decreased GPx3. These results suggest that GPx3 is an important factor for inhibition of APAP‑induced hepatotoxicity both in vivo and in vitro. To our knowledge, this is the first report to show a hepatoprotective role of cellular GPx3 against APAP‑induced liver damage.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Deneke SM and Fanburg BL: Regulation of cellular glutathione. Am J Physiol. 257:L163–L173. 1989.PubMed/NCBI

2 

Brigelius-Flohé R and Maiorino M: Glutathione peroxidases. Biochim Biophys Acta. 1830:3289–3303. 2013. View Article : Google Scholar

3 

Olson GE, Whitin JC, Hill KE, Winfrey VP, Motley AK, Austin LM, Deal J, Cohen HJ and Burk RF: Extracellular glutathione peroxidase (Gpx3) binds specifically to basement membranes of mouse renal cortex tubule cells. Am J Physiol Renal Physiol. 298:F1244–F1253. 2010. View Article : Google Scholar :

4 

Li YG, Ji DF, Zhong S, Shi LG, Hu GY and Chen S: Saponins from Panax japonicus protect against alcohol-induced hepatic injury in mice by upregulating the expression of GPX3, SOD1 and SOD3. Alcohol Alcohol. 45:320–331. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Rush JW and Sandiford SD: Plasma glutathione peroxidase in healthy young adults: Influence of gender and physical activity. Clin Biochem. 36:345–351. 2003. View Article : Google Scholar : PubMed/NCBI

6 

Nelson SD: Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis. 10:267–278. 1990. View Article : Google Scholar : PubMed/NCBI

7 

Dai G, He L, Chou N and Wan YJ: Acetaminophen metabolism does not contribute to gender difference in its hepatotoxicity in mouse. Toxicol Sci. 92:33–41. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Sheng Y, Liang Q, Deng Z, Ji L and Wang Z: Acetaminophen induced gender-dependent liver injury and the involvement of GCL and GPx. Drug Discov Ther. 7:78–83. 2013.PubMed/NCBI

9 

Botta D, Shi S, White CC, Dabrowski MJ, Keener CL, Srinouanprachanh SL, Farin FM, Ware CB, Ladiges WC, Pierce RH, et al: Acetaminophen-induced liver injury is attenuated in male glutamate-cysteine ligase transgenic mice. J Biol Chem. 281:28865–28875. 2006. View Article : Google Scholar : PubMed/NCBI

10 

McConnachie LA, Mohar I, Hudson FN, Ware CB, Ladiges WC, Fernandez C, Chatterton-Kirchmeier S, White CC, Pierce RH and Kavanagh TJ: Glutamate cysteine ligase modifier subunit deficiency and gender as determinants of acetaminophen-induced hepatotoxicity in mice. Toxicol Sci. 99:628–636. 2007. View Article : Google Scholar : PubMed/NCBI

11 

Masubuchi Y, Nakayama J and Watanabe Y: Sex difference in susceptibility to acetaminophen hepatotoxicity is reversed by buthionine sulfoximine. Toxicology. 287:54–60. 2011. View Article : Google Scholar : PubMed/NCBI

12 

Du K, Williams CD, McGill MR and Jaeschke H: Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase. Toxicol Appl Pharmacol. 281:58–66. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Mirochnitchenko O, Weisbrot-Lefkowitz M, Reuhl K, Chen L, Yang C and Inouye M: Acetaminophen toxicity. Opposite effects of two forms of glutathione peroxidase. J Biol Chem. 274:10349–10355. 1999. View Article : Google Scholar : PubMed/NCBI

14 

Kanno S, Tomizawa A and Yomogida S: Detecting mRNA Predictors of acetaminophen-induced hepatotoxicity in mouse blood using quantitative real-time PCR. Biol Pharm Bull. 39:440–445. 2016. View Article : Google Scholar : PubMed/NCBI

15 

Chandrasekaran VR, Periasamy S, Liu LL and Liu MY: 17β-Estradiol protects against acetaminophen-overdose-induced acute oxidative hepatic damage and increases the survival rate in mice. Steroids. 76:118–124. 2011. View Article : Google Scholar

16 

Baltgalvis KA, Greising SM, Warren GL and Lowe DA: Estrogen regulates estrogen receptors and antioxidant gene expression in mouse skeletal muscle. PLoS One. 5:e101642010. View Article : Google Scholar : PubMed/NCBI

17 

Kanno S, Ishikawa M, Takayanagi M, Takayanagi Y and Sasaki K: Potentiation of acetaminophen hepatotoxicity and mortality by doxapram in mice. Biol Pharm Bull. 21:934–937. 1998. View Article : Google Scholar : PubMed/NCBI

18 

Kanno S, Tomizawa A, Hiura T, Osanai Y, Kakuta M, Kitajima Y, Koiwai K, Ohtake T, Ujibe M and Ishikawa M: Melatonin protects on toxicity by acetaminophen but not on pharmacological effects in mice. Biol Pharm Bull. 29:472–476. 2006. View Article : Google Scholar : PubMed/NCBI

19 

Hori Y, Iwasaki Y, Kuroki Y, Komiyayama Y, Nakatani H and Namera A: Practical analysis of toxic substances useful for clinical toxicology–4–Acetaminophen. Chudoku Kenkyu. 15:385–390. 2002.

20 

Berridge MV, Herst PM and Tan AS: Tetrazolium dyes as tools in cell biology: New insights into their cellular reduction. Biotechnol Annu Rev. 11:127–152. 2005. View Article : Google Scholar : PubMed/NCBI

21 

Kanno S, Kurauchi K, Tomizawa A, Yomogida S and Ishikawa M: Pifithrin-alpha has a p53-independent cytoprotective effect on docosahexaenoic acid-induced cytotoxicity in human hepatocellular carcinoma HepG2 cells. Toxicol Lett. 232:393–402. 2015. View Article : Google Scholar

22 

Huh K, Shin US, Choi JW and Lee SI: Effect of sex hormones on lipid peroxidation in rat liver. Arch Pharm Res. 17:109–114. 1994. View Article : Google Scholar : PubMed/NCBI

23 

Gómez-Zubeldia MA, Hernandez R, Viguera J, Arbues JJ, Aparicio A and Millán JC: Effect of bilateral ovariectomy and ovarian steroid hormones on the antioxidant systems and plasma malondialdehyde levels in Wistar rats. Endocr Res. 26:97–107. 2000. View Article : Google Scholar : PubMed/NCBI

24 

Kumar S, Lata K, Mukhopadhyay S and Mukherjee TK: Role of estrogen receptors in pro-oxidative and anti-oxidative actions of estrogens: A perspective. Biochim Biophys Acta. 1800:1127–1135. 2010. View Article : Google Scholar : PubMed/NCBI

25 

Sugioka K, Shimosegawa Y and Nakano M: Estrogens as natural antioxidants of membrane phospholipid peroxidation. FEBS Lett. 210:37–39. 1987. View Article : Google Scholar : PubMed/NCBI

26 

Ruiz-Larrea MB, Leal AM, Martín C, Martínez R and Lacort M: Antioxidant action of estrogens in rat hepatocytes. Rev Esp Fisiol. 53:225–229. 1997.PubMed/NCBI

27 

Borrás C, Gambini J, Gómez-Cabrera MC, Sastre J, Pallardó FV, Mann GE and Viña J: 17beta-oestradiol up-regulates longevity- related, antioxidant enzyme expression via the ERK1 and ERK2[MAPK]/NFkappaB cascade. Aging Cell. 4:113–118. 2005. View Article : Google Scholar

28 

Priyanka HP, Krishnan HC, Singh RV, Hima L and Thyagarajan S: Estrogen modulates in vitro T cell responses in a concentration- and receptor-dependent manner: Effects on intracellular molecular targets and antioxidant enzymes. Mol Immunol. 56:328–339. 2013. View Article : Google Scholar : PubMed/NCBI

29 

Michiels C, Raes M, Toussaint O and Remacle J: Importance of Se-glutathione peroxidase, catalase, and Cu/Zn-SOD for cell survival against oxidative stress. Free Radic Biol Med. 17:235–248. 1994. View Article : Google Scholar : PubMed/NCBI

30 

Barrett CW, Ning W, Chen X, Smith JJ, Washington MK, Hill KE, Coburn LA, Peek RM, Chaturvedi R, Wilson KT, et al: Tumor suppressor function of the plasma glutathione peroxidase gpx3 in colitis-associated carcinoma. Cancer Res. 73:1245–1255. 2013. View Article : Google Scholar :

31 

He Y, Wang Y, Li P, Zhu S, Wang J and Zhang S: Identification of GPX3 epigenetically silenced by CpG methylation in human esophageal squamous cell carcinoma. Dig Dis Sci. 56:681–688. 2011. View Article : Google Scholar

32 

Peng DF, Razvi M, Chen H, Washington K, Roessner A, Schneider-Stock R and El-Rifai W: DNA hypermethylation regulates the expression of members of the Mu-class glutathione S-transferases and glutathione peroxidases in Barrett's adenocarcinoma. Gut. 58:5–15. 2009. View Article : Google Scholar

33 

Murawaki Y, Tsuchiya H, Kanbe T, Harada K, Yashima K, Nozaka K, Tanida O, Kohno M, Mukoyama T, Nishimuki E, et al: Aberrant expression of selenoproteins in the progression of colorectal cancer. Cancer Lett. 259:218–230. 2008. View Article : Google Scholar

34 

Qi X, Ng KT, Lian QZ, Liu XB, Li CX, Geng W, Ling CC, Ma YY, Yeung WH, Tu WW, et al: Clinical significance and therapeutic value of glutathione peroxidase 3 (GPx3) in hepatocellular carcinoma. Oncotarget. 5:11103–11120. 2014. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Kanno S, Tomizawa A, Yomogida S and Hara A: Glutathione peroxidase 3 is a protective factor against acetaminophen‑induced hepatotoxicity in vivo and in vitro. Int J Mol Med 40: 748-754, 2017.
APA
Kanno, S., Tomizawa, A., Yomogida, S., & Hara, A. (2017). Glutathione peroxidase 3 is a protective factor against acetaminophen‑induced hepatotoxicity in vivo and in vitro. International Journal of Molecular Medicine, 40, 748-754. https://doi.org/10.3892/ijmm.2017.3049
MLA
Kanno, S., Tomizawa, A., Yomogida, S., Hara, A."Glutathione peroxidase 3 is a protective factor against acetaminophen‑induced hepatotoxicity in vivo and in vitro". International Journal of Molecular Medicine 40.3 (2017): 748-754.
Chicago
Kanno, S., Tomizawa, A., Yomogida, S., Hara, A."Glutathione peroxidase 3 is a protective factor against acetaminophen‑induced hepatotoxicity in vivo and in vitro". International Journal of Molecular Medicine 40, no. 3 (2017): 748-754. https://doi.org/10.3892/ijmm.2017.3049
Copy and paste a formatted citation
x
Spandidos Publications style
Kanno S, Tomizawa A, Yomogida S and Hara A: Glutathione peroxidase 3 is a protective factor against acetaminophen‑induced hepatotoxicity in vivo and in vitro. Int J Mol Med 40: 748-754, 2017.
APA
Kanno, S., Tomizawa, A., Yomogida, S., & Hara, A. (2017). Glutathione peroxidase 3 is a protective factor against acetaminophen‑induced hepatotoxicity in vivo and in vitro. International Journal of Molecular Medicine, 40, 748-754. https://doi.org/10.3892/ijmm.2017.3049
MLA
Kanno, S., Tomizawa, A., Yomogida, S., Hara, A."Glutathione peroxidase 3 is a protective factor against acetaminophen‑induced hepatotoxicity in vivo and in vitro". International Journal of Molecular Medicine 40.3 (2017): 748-754.
Chicago
Kanno, S., Tomizawa, A., Yomogida, S., Hara, A."Glutathione peroxidase 3 is a protective factor against acetaminophen‑induced hepatotoxicity in vivo and in vitro". International Journal of Molecular Medicine 40, no. 3 (2017): 748-754. https://doi.org/10.3892/ijmm.2017.3049
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team