Environmental Health and Preventive Medicine

, Volume 21, Issue 6, pp 579–584 | Cite as

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

Short Communication

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.

Keywords

Carbon-tetrachloride Liver Hochu-ekki-to Oxidative stress 

Notes

Acknowledgments

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

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

References

  1. 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.CrossRefPubMedGoogle Scholar
  2. 2.
    Patel RP, Lang JD, Smith AB, Crawford JH. Redox therapeutics in hepatic ischemia reperfusion injury. World J Hepatol. 2014;6:1–8.PubMedPubMedCentralGoogle Scholar
  3. 3.
    McGregor D, Lang M. Carbon tetrachloride: genetic effects and other modes of action. Mutat Res. 1996;366:181–95.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 5.
    Recknagel RO, Glende EA Jr, Dolak JA, Waller RL. Mechanisms of carbon tetrachloride toxicity. Pharmacol Ther. 1989;43:139–54.CrossRefPubMedGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 20.
    Lee WM, Senior JR. Recognizing drug-induced liver injury: current problems, possible solutions. Toxicol Pathol. 2005;33:155–64.CrossRefPubMedGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 24.
    Onosaka S, Tanaka K, Cherian MG. Effects of cadmium and zinc on tissue levels of metallothionein. Environ Health Perspect. 1984;54:67–72.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 28.
    Szymanska JA, Swietlicka EA, Piotrowski JK. Protective effect of zinc in the hepatotoxicity of bromobenzene and acetaminophen. Toxicology. 1991;66:81–91.CrossRefPubMedGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefGoogle Scholar

Copyright information

© The Japanese Society for Hygiene 2016

Authors and Affiliations

  1. 1.College of PharmacyKinjo Gakuin UniversityNagoyaJapan
  2. 2.Faculty of NutritionKobe Gakuin UniversityKobeJapan

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