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Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields. Liver disease is associated with hepatic inflammation, tissue damage and altered liver function, and affects tens of millions of patients worldwide [1]. Numerous studies have been undertaken to investigate the biological activity of genipin and geniposide, including its effect on protein modulation [9-11], as well as its anti-inflammatory [5,12,13], anti-oxidative [5,14], immunosuppressive [15], antithrombotic [16], anti-angiogenic [5], anti-tumor [17-19] and neuroprotective effects [20-23]. The pharmacokinetics of geniposide, were investigated in a study that simultaneously estimated geniposide and genipin levels in mouse plasma after oral administration of Gardenia fruit [24]. In 2004, it was verified that geniposide is converted to genipin by intestinal bacteria and that genipin is transported to the liver via portal circulation and subjected to conjugation (mainly with glucuronides). Chronic liver injury is a common condition associated with various liver diseases, which often progress to fibrosis, cirrhosis, or even hepatocellular carcinoma [29]. In other studies, [32] geniposide suppressed AST and ALT activity and prevented the decreased glutathione (GSH) levels that accompanied administration of CCl4 to mice.
Alcoholic liver disease (ALD) is responsible for a large proportion of all liver diseases worldwide [33].
Geniposide has also been shown to have beneficial effects on bile secretion and liver injury.
Liver fibrosis results from excessive accumulation of extracellular matrix (ECM) proteins, and is a major cause of from chronic liver disease. Inchin-ko-to (TJ-135) is a herbal medicine used for treatment of icteric patients with cirrhosis.
Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and is the most common cause of chronic liver disease [51-56], present in 25 to 50% of diabetic patients [57].
Based on the current pre-clinical evidence, Samson and Bajaj [65] have shown that glucagon-like peptide-1(GLP-1) analogues and DPP4 inhibitors can improve hepatic steatosis. Fulminant hepatic failure is a life-threatening clinical syndrome that results in hepatocyte death.
Genipin has been shown to have marked anti-inflammatory and anti-angiogenic effects and inhibit both lipid peroxidation and nitric oxide production [5]. Hepatocellular carcinoma (HCC) is an extremely malignant human cancer with high metastatic potential. Genipin and geniposide have been shown to induce apoptosis in hepatoma cells Hep3B, cervical cancer cells, HeLa cells, prostate cancer cells PC3 and C6 glioma [77-80]. It was further demonstrated that the protective effect of geniposide on AFB1-induced hepatotoxicity in rats may be due to the hepatic tissue defense mechanisms that enhanced S-transferase (GST) activity for AFB1 detoxication and induced gamma-glutamylcysteine synthetase for GSH biosynthesis.
Further research is needed to more fully characterize the toxic effects of geniposide and genipin.
In this review, we describe and analyze the hepatoprotective effects of geniposide and its metabolite, genipin in liver disease. Wang SC, Liao HJ, Lee WC, Huang CM, Tsai TH (2008) Using orthogonal array to obtain gradient liquid chromatography conditions of enhanced peak intensity to determine geniposide and genipin with electrospray tandem mass spectrometry.
Kimura Y, Okuda H, Arichi S (1982) Effects of geniposide isolated from Gardenia jasminoides on metabolic alterations in high sugar diet-fed rats. Akao T, Kobashi K, Aburada M (1994) Enzymic studies on the animal and intestinal bacterial metabolism of geniposide. Kang JJ, Wang HW, Liu TY, Chen YC, Ueng TH (1997) Modulation of cytochrome P-450-dependent monooxygenases, glutathione and glutathione S-transferase in rat liver by geniposide from Gardenia jasminoides.
Kuo WH, Chou FP, Young SC, Chang YC, Wang CJ (2005) Geniposide activates GSH S-transferase by the induction of GST M1 and GST M2 subunits involving the transcription and phosphorylation of MEK-1 signaling in rat hepatocytes.
Koo HJ, Lim KH, Jung HJ, Park EH (2006) Anti-inflammatory evaluation of gardenia extract, geniposide and genipin.
Chang WL, Wang HY, Shi LS, Lai JH, Lin HC (2005) Immunosuppressive iridoids from the fruits of Gardenia jasminoides.
Suzuki Y, Kondo K, Ikeda Y, Umemura K (2001) Antithrombotic effect of geniposide and genipin in the mouse thrombosis model.
Hsu HY, Yang JJ, Lin SY, Lin CC (1997) Comparisons of geniposidic acid and geniposide on antitumor and radioprotection after sublethal irradiation. Yamazaki M, Sakura N, Chiba K, Mohri T (2001) Prevention of the neurotoxicity of the amyloid beta protein by genipin. Tanaka M, Yamazaki M, Chiba K (2009) Neuroprotective action of genipin on tunicamycin-induced cytotoxicity in neuro2a cells. Yamazaki M, Chiba K (2008) Genipin exhibits neurotrophic effects through a common signaling pathway in nitric oxide synthase expressing cells. Ueno K, Takeda Y, Iwasaki Y, Yoshizaki F (2001) Simultaneous estimation of geniposide and genipin in mouse plasma using high-performance liquid chromatography.
Tseng TY, Tsai TH (2004) Measurement of unbound geniposide in blood, liver, brain and bile of anesthetized rats: an application of pharmacokinetic study and its in?uence on acupuncture. Ye G, Zhu HY, Zhao HL, Xu B, Huang CG (2006) HPLC method for the determination and pharmacokinetic studies on geniposide in rat serum after oral administration of traditional Chinese medicinal preparation Yin-Zhi-Ku decoction. Hou YC, Tsai SY, Lai PY, Chen YS, Chao PD (2008) Metabolism and pharmacokinetics of genipin and geniposide in rats. Shang XT, Zhang L, Zu YG, Cao S (2012) Therapeutic effects of geniposide on chronic liver injury induced by CCl4 in rats. Zhang LM, He KZ, Ren ZJ, Pu Q (2005) Biochemical mechanism of hepatic protective effect of geniposide on liver-injured mice induced by CCl4. Fu T, Pu Q, Tan J (2007) Hepatoprotective effects of geniposide on acute alcoholic liver injury in mice. Mikami M, Takikawa H (2008) Effect of genipin on the biliary excretion of cholephilic compounds in rats. Goto H, Takikawa H (2010) Effect of genipin on cholestasis induced by estradiol-17beta-glucuronide and lithocholate-3-O-glucuornide in rats.
Peng J, Qian ZY, Liu TZ (2003) Comparative studies on hepatic protective and choleretic effect of geniposide and crocetin.
Lemoine M, Nayagam S, Thursz M (2013) Viral hepatitis in resource-limited countries and access to antiviral therapies: current and future challenges. Pinzani M, Rombouts K, Colagrande S (2005) Fibrosis in chronic liver diseases: diagnosis and management. Befeler AS, Di Bisceglie AM (2002) Hepatocellular carcinoma: diagnosis and treatment. Pungpapong S, Kim WR, Poterucha JJ (2007) Natural history of hepatitis B virus infection: an update for clinicians. Starley BQ, Calcagno CJ, Harrison SA (2010) Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection.
Baffy G, Brunt EM, Caldwell SH (2012) Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace.
Lin L, Guan X, Wang L, Tang Y (2010) [Influence of genipin and vitamin E on UCP2 and other correlation factors in non-alcoholic fatty liver disease]. Shi L, Sun J, Li L (2011) Antiobesity Effects of Geniposide on Monosodium Glutamate-induced Obese Mice.


Samson SL, Bajaj M (2013) Potential of incretin-based therapies for non-alcoholic fatty liver disease. Shakil AO, Kramer D, Mazariegos GV, Fung JJ, Rakela J (2000) Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria. Kim SJ, Kim JK, Lee DU, Kwak JH, Lee SM (2010) Genipin protects lipopolysaccharide-induced apoptotic liver damage in D-galactosamine-sensitized mice.
Ferlay J, Bray F, Pisani P, Parkin DM (2000) Cancer incidence, mortality and prevalence worldwide, version 1.0. Altekruse SF, McGlynn KA, Reichman ME (2009) Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. Hong HY, Kim BC (2007) Mixed lineage kinase 3 connects reactive oxygen species to c-Jun NH2-terminal kinase-induced mitochondrial apoptosis in genipin-treated PC3 human prostate cancer cells. Wang CJ, Wang SW, Lin JK (1991) Suppressive effect of geniposide on the hepatotoxicity and hepatic DNA binding of aflatoxin B1 in rats. Wang SW, Lai CY, Wang CJ (1992) Inhibitory effect of geniposide on aflatoxin B1-induced DNA repair synthesis in primary cultured rat hepatocytes. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Geniposide (Figure 1 left) is one of the main irioidglyco compounds isolated from Gardenia fruits and has been used for many years in Chinese medicine for treatment of hepatic disorders and inflammatory diseases [2]. Other studies have described the pharmacokinetics of geniposide after intravenous [25], and oral administration of Yin-Zhi-Ku decoction [26].
It is hydrolyzed in rat intestine by beta-D-glucosidases to form an aglycone genipin compound with choleretic properties [19]. Its main characteristics are hepatocyte necrosis or apoptosis, hepatocyte degeneration, hepatocyte steatosis, biliary silt lesions and hepatocyte inflammatory reactions. These findings suggest that a two-fold biochemical mechanism underlies the hepatic protective effect of geniposide. Acute alcoholic liver injury is a severe form of acute hepatocyte injury associated with significant morbidity and mortality. Considerable evidence [36] suggests that genipin exerts its choleretic function in a bile acid-independent way by modulating glutathione (GSH) levels in the liver.
Advanced hepatic fibrosis induced by chronic liver inflammation eventually progresses to cirrhosis [43-46]. It is thought that GLP-1 and its analogues activate multiple hepatocyte signal transduction pathways, with both AMP-activated protein kinase and Akt being proposed as be key players in the prevention of hepatic steatosis. It also suppresses Fas-induced hepatocyte apoptosis and reduces lethality associated with fulminant hepatic failure [30]. HCC accounts for over 85% of all liver cancer cases [72] and is newly diagnosed worldwide in more than half of million people annually [73]. Previous studies have also reported anti-migration and anti-invasion effects of genipin. Subsequent experiments [85] investigated the effects of geniposide on AFB1-induced DNA repair synthesis and AFB1 biotransformation in cultured rat hepatocytes. Acute toxicity studies indicate that geniposide at doses of 574 mgkg-1 and higher are associated with hepatic toxicity in rats. Both compounds exert extensive beneficial effects that offer potential therapeutic benefit to patients with liver disease. Geniposide is an irioidglyco compound isolated from Gardenia fruits which has been used for many years in Chinese medicine for the treatment of hepatic disorders and inflammatory diseases. Genipin (Figure 1 right), the metabolite of geniposide, is a natural product present in fruit of Gardenia jasminoides. Studies have shown that geniposide is not hydrolyzed by rat liver homogenate, even though it contained beta-D-glucosidase and esterase activities.
The same workers investigated whether ICKT or its ingredients (genipin) inhibited Fasmediated liver apoptosis in vivo. Geniposide reduces the production of the harmful CCl3 radical by decreasing the activities of CYP450 2E1, and at the same time strengthens the ability of GSH system to eliminate free radicals by increasing the activity of glutathione reductase and glutathione S-transferase.
Prognostic criteria have been developed to help predict disease severity, but its treatment remains a significant challenge [34]. They showed that geniposide reduced the mortality rate, prolonged survival and decreased serum AST and ALT activity.
Biliary secretion of bilirubin conjugates increased by 513% and GSH secretion was reduced by 336%.
They reported that genipin in combination with VitE increased mitochondrial membrane potential and markedly relieved adipose degeneration in liver cells. Interestingly, it has been shown that geniposide acts as a novel and selective agonist for GLP-1 receptors (GLP-1R) [63] providing further evidence of its potential role in the treatment of NASH. The prognosis is poor, and to date the only effective therapy is liver transplantation. HCC is the fifth most common malignant tumor in men and the seventh most common in women [72]. Genipin has been shown to suppress alpha-TN4 lens epithelial cells and subconjunctival fibroblast migration induced by TGF-β [81,82]. Evaluation of unscheduled DNA synthesis (UDS) indicated that geniposide reduced AFB1-induced DNA repair synthesis in a dose-dependent manner in hepatocyte cultures. Geniposide-induced GST activity was shown to be dose- and time–dependent, and was found to be mediated via the MEK pathway. The hepatotoxicity generally appeared 24 to 48 h after oral administration and was associated with oxidative stress, decreased total superoxide dismutase activity and increased malondialdehyde concentration in rat livers.
They found that the alcoholic extract and geniposide displayed hepatotoxicity, and that geniposide which was the main extract might be mainly responsible for this. Genipin, the metabolite of geniposide, is a natural product present in fruit of Gardenia jasminoides. PO1-3, does not share this property, even though both extracts share beta-D-glucosidase activity for p-nitrophenyl beta-D-glucopy-ranoside. Unconjugated genipin accounts for only 2% of the concentration of genipin-1-O-β- D-glucuronide.
Neither product had any effect on glutathione content or monooxygenase activity in kidney microsomes. They found that genipin, an intestinal bacterial metabolite of geniposide was a major ingredient in the active principle of ICKT. These changes were not present in multidrug resistance-associated protein 2 (Mrp2)-deficient rats. In these experiments, genipin significantly suppressed IFN-gamma production induced in con A-stimulated splenocyte cultures. In the USA and Europe, it is the most common nonneoplastic cause of death among hepatobiliary and digestive diseases.
These changes were accompanied by decreases in total cholesterol, triglycerides and fatty acids in serum and liver. It is the third most common cause of cancer mortality worldwide with incidence rates increasing annually [74].
Geniposide increased AFB1 metabolism and decreased the formation of aflatoxin M1(AFM1).


These results suggest that geniposide-induced detoxication is mediated by increased transcription of GST M1 and GST M2 resulting in enhanced GST activity. Further studies will be focused on both short- and long-term effects of geniposide and genipin in the treatment of liver disease and will seek to identify more clearly the complex cellular and biochemical mechanisms that underlie the disease processes.
The relative bioactivity of genipin and geniposide has been widely reported in many studies and the potential application of these compounds in the treatment of liver diseases has come to light. Genipin was shown to suppress Fas-mediated apoptosis in primary-cultured murine hepatocytes.
Based on these findings geniposide appears to have a hepatoprotective effect in acute alcoholic liver injury in mice. The protein mass of Mrp2 in the canalicular membrane vesicles (CMV), increased following exposure to genipin but there were no corresponding changes in mRNA levels. In addition, geniposide decreased serum ALT and AST levels in mice with CCl4 and acetaminophen (AAP)-induced liver injury whereas crocetin had no protective effect. This was accompanied by suppression of IL-1beta, IL-6, and IL-12p70 synthesis, together with decreased nitrite release from IFN-gamma-stimulated macrophages. Oral administration of TJ-135 reduced mortality and decreased the extent of liver necrosis and fibrosis.
This can lead to steatohepatitis (NASH), which is characterized by chronic inflammation, fibrosis and necrosis [58]. Geniposide also increased serum insulin levels and decreased serum tumor necrosis factor-α levels in high-fat diet rats. Despite the provision of different therapeutic approaches, the prognosis of HCC remains poor due to the high recurrence and metastatic rates [75,76]. These effects were possibly associated with an inhibitory effect of genipin on intracellular MMP-2 activity. The enzyme activities of glutathione S-transferase (GST) and GSH-peroxidase (GSH-Px) in AFB1-treated hepatocyte cultures were both enhanced in the presence of geniposide. Thus, the acute hepatotoxicity of geniposide at high doses was possibly related with oxidative stress, while geniposide at normal doses of 24.3 mgkg-1 were not associated with hepatotoxicity after repeated dosing [88]. This review summarizes current findings on the use of geniposide and genipin in the treatment of liver disease. Geniposide is hydrolyzed to aglycone genipin by beta-Dglycosidases which are bacterial enzymes found in the intestines and the liver [7,8] (Figure 2). A-44 and neither of the two beta-D-glucosidases from Ruminococcus spp PO1-3 hydrolyzed geniposide to genipin. Genipin sulfate was identified as the major metabolite in the circulation following oral administration of genipin or Gardenia fruit decoction to rats. Total hepatic glutathione content and hepatic cytosolic glutathione S-transferase activity were also increased. Twelve hours after the last dose, AST, ALT, AKP, NO were measured in serum and SOD, MDA, HYP, CAT, and GSH was evaluated in liver tissue.
It also inhibited the activation of caspase 3 and 8 in liver homogenates, and reduced triangle uppsi (m) levels in hepatocytes isolated from Jo2-treated mice. The same researchers reported that in immunoelectron microscope studies, there was a marked increase in Mrp2 density in the canalicular membrane (CM) and microvilli following exposure of liver tissue section to genipin. In the same mouse model geniposide and crocetin reduced MDA levels, and decreased GSH and glutathione peroxidase (GSH-Px). These results suggested that genipin may contribute to the protective effects of ICKT against conA hepatitis by modulating cytokine production. Cirrhosis, develops in 20% of patients with NASH [59] and is a risk factor for hepatocellular carcinoma (HCC), which is the third most common cause of cancer death worldwide [55,58]. Currently there are no effective chemotherapeutic agents that are capable of preventing metastasis.
Geniposide reduced AFB1-induced DNA repair synthesis by increasing AFB1 detoxication metabolism. These findings suggested that genipin may enhance the bile acid-independent secretory capacity of hepatocytes, by stimulating exocytosis and inserting Mrp2 in the bile canaliculi. Histological degeneration was minimized with geniposide which exerted more significant effects than crocetin.
DNA synthesis of stellate cells activated in vitro, after isolation from normal rat liver, was decreased in a doserelated manner after exposure to TJ-135. Disturbingly, HCC also can form in the setting of NASH without a background of cirrhosis [60,61]. These changes were thought to be associated with increased superoxide dismutase and decreased malondialdehyde levels in the liver.
In these experiment geniposide inhibited food intake, decreased body weight and reduced blood levels of triglycerides and cholesterol. These findings provide a possible mechanism for the chemopreventive activity of geniposide. A-44 in pig liver were unable to hydrolyze geniposide to geniposidic acid, but they did hydrolyze genipin to an aglycone of geniposidic acid. These findings provided evidence to suggest that geniposide was effective in preventing chronic liver injury induced by CCl4 in rats.
Based on these findings, the authors concluded that geniposide was the chief effective component of Gardenia jasminoides Eillis. This was accompanied by a decrease in smooth muscle alpha actin expression and contractility.
Lifestyle changes and weight loss are difficult to achieve in most patients, highlighting the urgent need for an effective pharmacologic treatment for NAFLD. The underlying mechanism by which geniposide protects against hepatic steatosis may, therefore, be associated with its antioxidant actions its ability to regulate adipocytokine release and normalization of PPARα expression.
Taken together, these findings suggest that the anti-apoptotic activity of genipin is mediated by interference with MPT and that this may be a possible mechanism for the therapeutic effects of ICKT.
These findings suggest that genipin induced apoptosis in hepatoma cells is mediated by NADPH oxidase-dependent generation of reactive oxygen species (ROS), resulting in downstream activation of c-Jun NH2-terminal kinase (JNK). Thus, following oral administration of geniposide, genipin is produced in the intestine, absorbed into the circulation and transported to the liver where it acts as a choleretic [7].
The choleretic effect of genipin was considered to be predominantly due to increased biliary glutathione excretion by genipin, rather than to the biliary excretion of glucuronide. Genipin markedly decreased stellate cell activation without affecting synthesis of proteins other than collagen. These results indicate that TJ-135 may have a therapeutic role in the treatment of liver fibrosis and portal hypertension.
Its effects are secondary to suppression of activated hepatic stellate cell function by genipin (the absorbed form of its component).



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