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Kampo formula “Hochu-ekki-to” suppressed carbon tetrachloride-induced hepatotoxicity in mice

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Environmental Health and Preventive Medicine Aims and scope

Abstract

Objective

The aim of this study was to investigate whether pretreatment with the Japanese herbal medicine “Hochu-ekki-to” (TJ-41) has an ameliorative effect on carbon tetrachloride (CCl4)-induced hepatotoxicity through anorexia prevention.

Methods

Twenty-four hours before CCl4 injection, TJ-41 or saline solution was intraperitoneally administered. Furthermore, 24 h after TJ-41 injection, mice were intraperitoneally administered 1.6 g/kg CCl4 or olive oil. Moreover, 24 h after CCl4/olive oil injection, mice from each group were euthanized and bled for plasma analysis.

Results

Mice injected with CCl4 exhibited severe anorexia. Moreover, CCl4 increased the plasma levels of hepatic injury markers (i.e., alanine aminotransferase and aspartate aminotransferase) as well as lipid peroxidation and hepatic Ca levels. Pretreatment with TJ-41 recovered the CCl4-induced anorexia and plasma levels of the hepatic injury markers. Moreover, CCl4-induced lipid peroxidation and hepatic Ca levels decreased upon TJ-41 pretreatment. In addition, hepatic metallothionein levels in the TJ-41 + CCl4-treated group were decreased by >50 % compared with the levels in the TJ-41-treated group, implying that metallothionein was consumed by CCl4-induced radicals.

Conclusion

Our results suggest that TJ-41 attenuates CCl4-induced hepatotoxicity, presumably by the induction of metallothionein, which in turn scavenges radicals induced by CCl4 exposure.

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References

  1. Ma JQ, Ding J, Zhang L, Liu CM. Hepatoprotective properties of sesamin against CCl4 induced oxidative stress-mediated apoptosis in mice via JNK pathway. Food Chem Toxicol. 2014;64:41–8.

    Article  CAS  PubMed  Google Scholar 

  2. Patel RP, Lang JD, Smith AB, Crawford JH. Redox therapeutics in hepatic ischemia reperfusion injury. World J Hepatol. 2014;6:1–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. McGregor D, Lang M. Carbon tetrachloride: genetic effects and other modes of action. Mutat Res. 1996;366:181–95.

    Article  CAS  PubMed  Google Scholar 

  4. Weber LW, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 2003;33:105–36.

    Article  CAS  PubMed  Google Scholar 

  5. Recknagel RO, Glende EA Jr, Dolak JA, Waller RL. Mechanisms of carbon tetrachloride toxicity. Pharmacol Ther. 1989;43:139–54.

    Article  CAS  PubMed  Google Scholar 

  6. Wang T, Shankar K, Ronis MJ, Mehendale HM. Mechanisms and outcomes of drug- and toxicant-induced liver toxicity in diabetes. Crit Rev Toxicol. 2007;37:413–59.

    Article  CAS  PubMed  Google Scholar 

  7. Ko HJ, Chen JH, Ng LT. Hepatoprotection of Gentiana scabra extract and polyphenols in liver of carbon tetrachloride-intoxicated mice. J Environ Pathol Toxicol Oncol. 2011;30:179–87.

    Article  CAS  PubMed  Google Scholar 

  8. Knockaert L, Berson A, Ribault C, Prost PE, Fautrel A, Pajaud J, et al. Carbon tetrachloride-mediated lipid peroxidation induces early mitochondrial alterations in mouse liver. Lab Invest. 2012;92:396–410.

    Article  CAS  PubMed  Google Scholar 

  9. Huang GJ, Deng JS, Huang SS, Lee CY, Hou WC, Wang SY, et al. Hepatoprotective effects of eburicoic acid and dehydroeburicoic acid from Antrodia camphorata in a mouse model of acute hepatic injury. Food Chem. 2013;141:3020–7.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang F, Wang X, Qiu X, Wang J, Fang H, Wang Z, et al. The protective effect of esculentoside a on experimental acute liver injury in mice. PLoS One. 2014;9:e113107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Suzuki T, Takano I, Nagai F, Fujitani T, Ushiyama K, Okubo T, et al. Suppressive effects of Hochu-ekki-to, a traditional Chinese medicine, on IgE production and histamine release in mice immunized with ovalbumin. Biol Pharm Bull. 1999;22:1180–4.

    Article  CAS  PubMed  Google Scholar 

  12. Mori K, Kido T, Daikuhara H, Sakakibara I, Sakata T, Shimizu K, et al. Effect of Hochu-ekki-to (TJ-41), a Japanese herbal medicine, on the survival of mice infected with influenza virus. Antiviral Res. 1999;44:103–11.

    Article  CAS  PubMed  Google Scholar 

  13. Qi F, Li A, Inagaki Y, Gao J, Li J, Kokudo N, et al. Chinese herbal medicines as adjuvant treatment during chemo- or radio-therapy for cancer. Biosci Trends. 2010;4:297–307.

    PubMed  Google Scholar 

  14. Wong FW, Chan WY, Lee SS. Resistance to carbon tetrachloride-induced hepatotoxicity in mice which lack CYP2E1 expression. Toxicol Appl Pharmacol. 1998;153:109–18.

    Article  CAS  PubMed  Google Scholar 

  15. Al-Sayed E, Abdel-Daim MM. Protective role of Cupressuflavone from Cupressus macrocarpa against carbon tetrachloride-induced hepato- and nephrotoxicity in mice. Planta Med. 2014;80:1665–71.

    Article  CAS  PubMed  Google Scholar 

  16. Shi H, Liu X, Tang G, Liu H, Zhang Y, Zhang B, et al. Ethanol extract of Portulaca oleracea L. reduced the carbon tetrachloride induced liver injury in mice involving enhancement of NF-kappaB activity. Am. J Transl Res. 2014;6:746–55.

    Google Scholar 

  17. Yoshioka H, Usuda H, Nonogaki T, Onosaka S. Carbon tetrachloride-induced lethality in mouse is prevented by multiple pretreatment with zinc sulfate. J Toxicol Sci. 2016;41:55–63.

    Article  PubMed  Google Scholar 

  18. Yoshioka H, Usuda H, Fukuishi N, Nonogaki T, Onosaka S. Carbon tetrachloride-induced nephrotoxicity in mice is prevented by pretreatment with zinc sulfate. Biol Pharm Bull. 2016;39:1042–6.

    Article  CAS  PubMed  Google Scholar 

  19. Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA. 1999;281:1014–8.

    Article  CAS  PubMed  Google Scholar 

  20. Lee WM, Senior JR. Recognizing drug-induced liver injury: current problems, possible solutions. Toxicol Pathol. 2005;33:155–64.

    Article  CAS  PubMed  Google Scholar 

  21. Recknagel RO, Lowrey K, Waller RL, Glende Jr EA. Destruction of microsomal calcium pump activity: a possible secondary mechanism in BrCCl3 and CCl4 liver cell injury. Adv Exp Med Biol. 1981;136(Pt A):619–31.

    PubMed  Google Scholar 

  22. Hsouna AB, Saoudi M, Trigui M, Jamoussi K, Boudawara T, Jaoua S, et al. Characterization of bioactive compounds and ameliorative effects of Ceratonia siliqua leaf extract against CCl(4) induced hepatic oxidative damage and renal failure in rats. Food Chem Toxicol. 2011;49:3183–91.

    Article  CAS  PubMed  Google Scholar 

  23. Sato M, Kondoh M. Recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals. Tohoku J Exp Med. 2002;196:9–22.

    Article  CAS  PubMed  Google Scholar 

  24. Onosaka S, Tanaka K, Cherian MG. Effects of cadmium and zinc on tissue levels of metallothionein. Environ Health Perspect. 1984;54:67–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Min KS, Terano Y, Onosaka S, Tanaka K. Induction of hepatic metallothionein by nonmetallic compounds associated with acute-phase response in inflammation. Toxicol Appl Pharmacol. 1991;111:152–62.

    Article  CAS  PubMed  Google Scholar 

  26. Chengelis CP, Dodd DC, Means JR, Kotsonis FN. Protection by zinc against acetaminophen induced hepatotoxicity in mice. Fundam Appl Toxicol. 1986;6:278–84.

    Article  CAS  PubMed  Google Scholar 

  27. Saito C, Yan HM, Artigues A, Villar MT, Farhood A, Jaeschke H. Mechanism of protection by metallothionein against acetaminophen hepatotoxicity. Toxicol Appl Pharmacol. 2010;242:182–90.

    Article  CAS  PubMed  Google Scholar 

  28. Szymanska JA, Swietlicka EA, Piotrowski JK. Protective effect of zinc in the hepatotoxicity of bromobenzene and acetaminophen. Toxicology. 1991;66:81–91.

    Article  CAS  PubMed  Google Scholar 

  29. Liu J, Liu Y, Michalska AE, Choo KH, Klaassen CD. Metallothionein plays less of a protective role in cadmium-metallothionein-induced nephrotoxicity than in cadmium chloride-induced hepatotoxicity. J Pharmacol Exp Ther. 1996;276:1216–23.

    CAS  PubMed  Google Scholar 

  30. Park JD, Liu Y, Klaassen CD. Protective effect of metallothionein against the toxicity of cadmium and other metals(1). Toxicology. 2001;163:93–100.

    Article  CAS  PubMed  Google Scholar 

  31. Itoh N, Morishita Y, Tanaka T, Muto N, Kobayashi M, Kitagawa I, et al. Metallothionein induction and hepatoprotection by echinoside A and sakuraso-saponin. Phytoth Res. 1997;11:132–5.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors thank Dr. Kenichi Saeki and Dr. Nobuyuki Fukuishi (Kinjo Gakuin University, Japan) for their kind suggestions.

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Authors and Affiliations

  1. College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyamaku, Nagoya, 463-8521, Aichi, Japan

    Hiroki Yoshioka, Shiori Fukaya, Tsunemasa Nonogaki & Akito Nagatsu

  2. Faculty of Nutrition, Kobe Gakuin University, 518 Arise, Ikawadani-cho, Nishi-ku, Kobe, 651-2180, Hyogo, Japan

    Hiroki Yoshioka & Satomi Onosaka

Authors
  1. Hiroki Yoshioka
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  2. Shiori Fukaya
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  3. Satomi Onosaka
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  4. Tsunemasa Nonogaki
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  5. Akito Nagatsu
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Correspondence to Hiroki Yoshioka or Akito Nagatsu.

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Yoshioka, H., Fukaya, S., Onosaka, S. et al. Kampo formula “Hochu-ekki-to” suppressed carbon tetrachloride-induced hepatotoxicity in mice. Environ Health Prev Med 21, 579–584 (2016). https://doi.org/10.1007/s12199-016-0571-x

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  • DOI: https://doi.org/10.1007/s12199-016-0571-x

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