Current scenario for the hepatoprotective effects of Inchinkoto, a traditional herbal medicine, and its clinical application in liver surgery: A review
Corresponding Author
Yukihiro Yokoyama
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
Correspondence: Dr Yukihiro Yokoyama, Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Email: [email protected]Search for more papers by this authorMasato Nagino
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorCorresponding Author
Yukihiro Yokoyama
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
Correspondence: Dr Yukihiro Yokoyama, Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Email: [email protected]Search for more papers by this authorMasato Nagino
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorAbstract
Inchinkoto (ICKT) is one of the most commonly used herbal medicines as a hepatoprotective agent. Among the numerous chemical compounds included in ICKT, geniposide is the most abundant component. Geniposide, after p.o. intake, is converted to the active metabolite genipin by intestinal bacteria and is absorbed in the portal circulation. The biological properties of ICKT and genipin have been studied in numerous experiments. Administration of ICKT or genipin exerts choleretic effects through upregulation of multidrug resistance-associated protein 2 in hepatocytes. ICKT also exerts an anti-apoptotic action through inhibition of transforming growth factor-β1- or tumor necrosis factor-α-dependent signaling pathways. The excessive inflammatory response induced by various hepatic stresses is also attenuated by ICKT pre-administration. Moreover, ICKT upregulates antioxidant enzymes in the liver under conditions of oxidative stress. These experimental results suggest potential benefit of ICKT in liver disease and particularly in hepatic surgery, which justify further well-designed controlled clinical study. To date, however, clinical data regarding the benefit of ICKT for liver surgery are rare. This review article summarized and discussed recent evidence relating to the hepatoprotective effects of ICKT in the field of basic and clinical science.
References
- 1 Kono T, Kaneko A, Omiya Y, Ohbuchi K, Ohno N, Yamamoto M. Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine. Am J Physiol Gastrointest Liver Physiol 2013; 304: G428–436.
- 2 Takeda H, Sadakane C, Hattori T et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology 2008; 134: 2004–2013.
- 3 Shoda J, Miura T, Utsunomiya H et al. Genipin enhances Mrp2 (Abcc2)-mediated bile formation and organic anion transport in rat liver. Hepatology 2004; 39 (1): 167–178.
- 4 Wang L, Zhang RM, Liu GY et al. Chinese herbs in treatment of influenza: a randomized, double-blind, placebo-controlled trial. Respir Med 2010; 104: 1362–1369.
- 5 Satoh N, Sakai S, Kogure T et al. A randomized double blind placebo-controlled clinical trial of Hochuekkito, a traditional herbal medicine, in the treatment of elderly patients with weakness N of one and responder restricted design. Phytomedicine 2005; 12: 549–554.
- 6 Iwasaki K, Satoh-Nakagawa T, Maruyama M et al. A randomized, observer-blind, controlled trial of the traditional Chinese medicine Yi-Gan San for improvement of behavioral and psychological symptoms and activities of daily living in dementia patients. J Clin Psychiatry 2005; 66: 248–252.
- 7 Urata Y, Yoshida S, Irie Y et al. Treatment of asthma patients with herbal medicine TJ-96: a randomized controlled trial. Respir Med 2002; 96: 469–474.
- 8 Yamamoto M, Miura N, Ohtake N et al. Genipin, a metabolite derived from the herbal medicine Inchin-ko-to, and suppression of Fas-induced lethal liver apoptosis in mice. Gastroenterology 2000; 118: 380–389.
- 9 Yamamoto M, Ogawa K, Morita M, Fukuda K, Komatsu Y. The herbal medicine Inchin-ko-to inhibits liver cell apoptosis induced by transforming growth factor beta 1. Hepatology 1996; 23: 552–559.
- 10 Okada K, Shoda J, Kano M et al. Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers. Am J Physiol Gastrointest Liver Physiol 2007; 292: G1450–1463.
- 11 Leu JI, Crissey MA, Taub R. Massive hepatic apoptosis associated with TGF-beta1 activation after Fas ligand treatment of IGF binding protein-1-deficient mice. J Clin Invest 2003; 111 (1): 129–139.
- 12 Kobayashi H, Horikoshi K, Yamataka A, Lane GJ, Yamamoto M, Miyano T. Beneficial effect of a traditional herbal medicine (inchin-ko-to) in postoperative biliary atresia patients. Pediatr Surg Int 2001; 17: 386–389.
- 13 Watanabe S, Yokoyama Y, Oda K et al. Choleretic effect of inchinkoto, a herbal medicine, on livers of patients with biliary obstruction due to bile duct carcinoma. Hepatol Res 2009; 39: 247–255.
- 14 Kaiho T, Tsuchiya S, Yanagisawa S et al. Effect of the herbal medicine Inchin-Ko-To for serum bilirubin in hepatectomized patients. Hepatogastroenterology 2008; 55 (81): 150–154.
- 15 Huang W, Zhang J, Moore DD. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J Clin Invest 2004; 113 (1): 137–143.
- 16 Takeuchi S, Goto T, Mikami K et al. Genipin prevents fulminant hepatic failure resulting in reduction of lethality through the suppression of TNF-alpha production. Hepatol Res 2005; 33: 298–305.
- 17 Yamashiki M, Mase A, Arai I et al. Effects of the Japanese herbal medicine “Inchinko-to” (TJ-135) on concanavalin A-induced hepatitis in mice. Clin Sci (Lond) 2000; 99: 421–431.
- 18 Kawai K, Yokoyama Y, Kokuryo T, Watanabe K, Kitagawa T, Nagino M. Inchinkoto, an herbal medicine, exerts beneficial effects in the rat liver under stress with hepatic ischemia-reperfusion and subsequent hepatectomy. Ann Surg 2010; 251: 692–700.
- 19 Matsuura T, Kaibori M, Araki Y et al. Japanese herbal medicine, inchinkoto, inhibits inducible nitric oxide synthase induction in interleukin-1beta-stimulated hepatocytes. Hepatol Res 2012; 42 (1): 76–90.
- 20 Koo HJ, Song YS, Kim HJ et al. Antiinflammatory effects of genipin, an active principle of gardenia. Eur J Pharmacol 2004; 495: 201–208.
- 21 Imanishi Y, Maeda N, Otogawa K et al. Herb medicine Inchin-ko-to (TJ-135) regulates PDGF-BB-dependent signaling pathways of hepatic stellate cells in primary culture and attenuates development of liver fibrosis induced by thioacetamide administration in rats. J Hepatol 2004; 41: 242–250.
- 22 Sakaida I, Tsuchiya M, Kawaguchi K, Kimura T, Terai S, Herbal OK. medicine Inchin-ko-to (TJ-135) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. J Hepatol 2003; 38: 762–769.
- 23 Ikeda H, Nagashima K, Yanase M et al. The herbal medicine inchin-ko-to (TJ-135) induces apoptosis in cultured rat hepatic stellate cells. Life Sci 2006; 78: 2226–2233.
- 24 Chu CY, Tseng TH, Hwang JM, Chou FP, Wang CJ. Protective effects of capillarisin on tert-butylhydroperoxide-induced oxidative damage in rat primary hepatocytes. Arch Toxicol 1999; 73: 263–268.
- 25 Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med 1998; 339: 1217–1227.
- 26 Geier A, Dietrich CG, Lammert F et al. Regulation of organic anion transporters in a new rat model of acute and chronic cholangitis resembling human primary sclerosing cholangitis. J Hepatol 2002; 36: 718–724.
- 27 Kullak-Ublick GA, Baretton GB, Oswald M, Renner EL, Paumgartner G, Beuers U. Expression of the hepatocyte canalicular multidrug resistance protein (MRP2) in primary biliary cirrhosis. Hepatol Res 2002; 23 (1): 78–82.
- 28 Trauner M, Arrese M, Soroka CJ et al. The rat canalicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis. Gastroenterology 1997; 113 (1): 255–264.
- 29 Yamada T, Arai T, Nagino M et al. Impaired expression of hepatic multidrug resistance protein 2 is associated with posthepatectomy hyperbilirubinemia in patients with biliary cancer. Langenbecks Arch Surg 2005; 390: 421–429.
- 30 Bolder U, Ton-Nu HT, Schteingart CD, Frick E, Hofmann AF. Hepatocyte transport of bile acids and organic anions in endotoxemic rats: impaired uptake and secretion. Gastroenterology 1997; 112 (1): 214–225.
- 31 Bossard R, Stieger B, O'Neill B, Fricker G, Meier PJ. Ethinylestradiol treatment induces multiple canalicular membrane transport alterations in rat liver. J Clin Invest 1993; 91: 2714–2720.
- 32 Kanzler S, Galle PR. Apoptosis and the liver. Semin Cancer Biol 2000; 10: 173–184.
- 33 Brouckaert P, Fiers W. Tumor necrosis factor and the systemic inflammatory response syndrome. Curr Top Microbiol Immunol 1996; 216: 167–187.
- 34 Osawa Y, Nagaki M, Banno Y et al. Possible involvement of reactive oxygen species in d-galactosamine-induced sensitization against tumor necrosis factor-alpha-induced hepatocyte apoptosis. J Cell Physiol 2001; 187: 374–385.
- 35 Arab JP, Ramirez C, Munoz P et al. Effects of Japanese herbal medicine Inchin-ko-to on endotoxin-induced cholestasis in the rat. Ann Hepatol 2009; 8: 228–233.
- 36 Szabo C, Billiar TR. Novel roles of nitric oxide in hemorrhagic shock. Shock 1999; 12 (1): 1–9.
- 37 Lee VG, Johnson ML, Baust J, Laubach VE, Watkins SC, Billiar TR. The roles of iNOS in liver ischemia-reperfusion injury. Shock 2001; 16: 355–360.
- 38 Carnovale CE, Scapini C, Alvarez ML, Favre C, Monti J, Carrillo MC. Nitric oxide release and enhancement of lipid peroxidation in regenerating rat liver. J Hepatol 2000; 32: 798–804.
- 39 Watanabe N, Miura S, Zeki S, Ishii H. Hepatocellular oxidative DNA injury induced by macrophage-derived nitric oxide. Free Radic Biol Med 2001; 30: 1019–1028.
- 40 Mizumoto M, Arii S, Furutani M et al. NO as an indicator of portal hemodynamics and the role of iNOS in increased NO production in CCl4-induced liver cirrhosis. J Surg Res 1997; 70: 124–133.
- 41 Lee KS, Buck M, Houglum K, Chojkier M. Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest 1995; 96: 2461–2468.
- 42 Pinzani M, Milani S, De Franco R et al. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 1996; 110: 534–548.
- 43 Garcia-Trevijano ER, Iraburu MJ, Fontana L et al. Transforming growth factor beta1 induces the expression of alpha1(I) procollagen mRNA by a hydrogen peroxide-C/EBPbeta-dependent mechanism in rat hepatic stellate cells. Hepatology 1999; 29: 960–970.
- 44 Davis BH, Rapp UR, Davidson NO. Retinoic acid and transforming growth factor beta differentially inhibit platelet-derived-growth-factor-induced Ito-cell activation. Biochem J 1991; 278 (Pt 1): 43–47.
- 45 Friedman SL, Arthur MJ. Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors. J Clin Invest 1989; 84: 1780–1785.
- 46 Gressner AM. Cytokines and cellular crosstalk involved in the activation of fat-storing cells. J Hepatol 1995; 22 (2 Suppl): 28–36.
- 47 Ikeda K, Wakahara T, Wang YQ, Kadoya H, Kawada N, Kaneda K. In vitro migratory potential of rat quiescent hepatic stellate cells and its augmentation by cell activation. Hepatology 1999; 29: 1760–1767.
- 48 Inao M, Mochida S, Matsui A et al. Japanese herbal medicine Inchin-ko-to as a therapeutic drug for liver fibrosis. J Hepatol 2004; 41: 584–591.
- 49 Taylor DE, Ghio AJ, Piantadosi CA. Reactive oxygen species produced by liver mitochondria of rats in sepsis. Arch Biochem Biophys 1995; 316 (1): 70–76.
- 50 Spolarics Z. Endotoxin stimulates gene expression of ROS-eliminating pathways in rat hepatic endothelial and Kupffer cells. Am J Physiol 1996; 270 (4 Pt 1): G660–666.
- 51 Bilzer M, Paumgartner G, Gerbes AL. Glutathione protects the rat liver against reperfusion injury after hypothermic preservation. Gastroenterology 1999; 117 (1): 200–210.
- 52 Liu TZ, Lee KT, Chern CL, Cheng JT, Stern A, Tsai LY. Free radical-triggered hepatic injury of experimental obstructive jaundice of rats involves overproduction of proinflammatory cytokines and enhanced activation of nuclear factor kappaB. Ann Clin Lab Sci 2001; 31: 383–390.
- 53 Kalish GH, Di Luzio NR. Peroxidation of liver lipids in the pathogenesis of the ethanol-induced fatty liver. Science 1966; 152 (3727): 1390–1392.
- 54 Ji B, Ito K, Sekine S, Tajima A, Horie T. Ethacrynic-acid-induced glutathione depletion and oxidative stress in normal and Mrp2-deficient rat liver. Free Radic Biol Med 2004; 37: 1718–1729.
- 55 Kanz MF, Dugas TR, Liu H, Santa Cruz V. Glutathione depletion exacerbates methylenedianiline toxicity to biliary epithelial cells and hepatocytes in rats. Toxicol Sci 2003; 74: 447–456.
- 56 Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science 1987; 235 (4792): 1043–1046.
- 57 Kikuchi G, Yoshida T, Noguchi M. Heme oxygenase and heme degradation. Biochem Biophys Res Commun 2005; 338 (1): 558–567.
- 58 Ishii T, Itoh K, Takahashi S et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 2000; 275 (21): 16023–16029.
- 59 Hayashi A, Suzuki H, Itoh K, Yamamoto M, Sugiyama Y. Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts. Biochem Biophys Res Commun 2003; 310: 824–829.
- 60 Hayes JD, McMahon M. Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. Cancer Lett 2001; 174: 103–113.
- 61 Itoh K, Chiba T, Takahashi S et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 1997; 236: 313–322.
- 62 Wang GF, Wu SY, Rao JJ et al. Genipin inhibits endothelial exocytosis via nitric oxide in cultured human umbilical vein endothelial cells. Acta Pharmacol Sin 2009; 30: 589–596.
- 63 Suzuki Y, Kondo K, Ikeda Y, Umemura K. Antithrombotic effect of geniposide and genipin in the mouse thrombosis model. Planta medica 2001; 67: 807–810.
- 64 Yamazaki M, Chiba K. Genipin exhibits neurotrophic effects through a common signaling pathway in nitric oxide synthase-expressing cells. Eur J Pharmacol 2008; 581: 255–261.
- 65 Yamazaki M, Chiba K, Mohri T, Hatanaka H. Activation of the mitogen-activated protein kinase cascade through nitric oxide synthesis as a mechanism of neuritogenic effect of genipin in PC12h cells. Journal of neurochemistry 2001; 79 (1): 45–54.
- 66 Yamazaki M, Chiba K, Yoshikawa C. Genipin suppresses A23187-induced cytotoxicity in neuro2a cells. Biol Pharm Bull 2009; 32: 1043–1046.
- 67 Tanaka M, Yamazaki M, Chiba K. Neuroprotective action of genipin on tunicamycin-induced cytotoxicity in neuro2a cells. Biol Pharm Bull 2009; 32: 1220–1223.
- 68 Lee SO, Jeong YJ, Kim M, Kim CH, Lee IS. Suppression of PMA-induced tumor cell invasion by capillarisin via the inhibition of NF-kappaB-dependent MMP-9 expression. Biochem Biophys Res Commun 2008; 366: 1019–1024.
- 69 Cao H, Feng Q, Xu W et al. Genipin induced apoptosis associated with activation of the c-Jun NH2-terminal kinase and p53 protein in HeLa cells. Biol Pharm Bull 2010; 33: 1343–1348.
- 70 Kitano A, Saika S, Yamanaka O et al. Genipin suppresses subconjunctival fibroblast migration, proliferation and myofibroblast transdifferentiation. Ophthalmic Res 2006; 38: 355–360.
- 71 Kitano A, Saika S, Yamanaka O et al. Genipin suppression of fibrogenic behaviors of the alpha-TN4 lens epithelial cell line. J Cataract Refract Surg 2006; 32: 1727–1735.
- 72 Zhang CY, Parton LE, Ye CP et al. Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets. Cell metabolism 2006; 3: 417–427.
- 73 Munekage M, Kitagawa H, Ichikawa K et al. Pharmacokinetics of daikenchuto, a traditional Japanese medicine (kampo) after single oral administration to healthy Japanese volunteers. Drug Metabolism and Disposition: the Biological Fate of Chemicals 2011; 39: 1784–1788.
- 74 Yim JS, Kim YS, Moon SK et al. Metabolic activities of ginsenoside Rb1, baicalin, glycyrrhizin and geniposide to their bioactive compounds by human intestinal microflora. Biol Pharm Bull 2004; 27: 1580–1583.