A Network-Based Pharmacology Study of the Herb-Induced Liver Injury Potential of Traditional Hepatoprotective Chinese Herbal Medicines

Herbal medicines are widely used for treating liver diseases and generally regarded as safe due to their extensive use in Traditional Chinese Medicine practice for thousands of years. However, in recent years, there have been increased concerns regarding the long-term risk of Herb-Induced Liver Injury (HILI) in patients with liver dysfunction. Herein, two representative Chinese herbal medicines: one—Xiao-Chai-Hu-Tang (XCHT)—a composite formula, and the other—Radix Polygoni Multiflori (Heshouwu)—a single herb, were analyzed by network pharmacology study. Based on the network pharmacology framework, we exploited the potential HILI effects of XCHT and Heshouwu by predicting the molecular mechanisms of HILI and identified the potential hepatotoxic ingredients in XCHT and Heshouwu. According to our network results, kaempferol and thymol in XCHT and rhein in Heshouwu exhibit the largest number of liver injury target connections, whereby CASP3, PPARG and MCL1 may be potential liver injury targets for these herbal medicines. This network pharmacology assay might serve as a useful tool to explore the underlying molecular mechanism of HILI. Based on the theoretical predictions, further experimental verification should be performed to validate the accuracy of the predicted interactions between herbal ingredients and protein targets in the future.

[1]  S. Itoh,et al.  Liver injuries induced by herbal medicine, Syo-saiko-to (xiao-chai-hu-tang) , 1995, Digestive Diseases and Sciences.

[2]  Chien-Hung Chen,et al.  Differential Role of p38 in IL-1α Induction of MMP-9 and MMP-13 in an Established Liver Myofibroblast Cell Line , 2003, Journal of Biomedical Science.

[3]  Liang Chen,et al.  Anti-fibrotic effect of Cordyceps sinensis polysaccharide: Inhibiting HSC activation, TGF-β1/Smad signalling, MMPs and TIMPs , 2013, Experimental biology and medicine.

[4]  H. Farrar,et al.  Evaluation of Occult Acetaminophen Hepatotoxicity in Hospitalized Children Receiving Acetaminophen , 2001, Clinical pediatrics.

[5]  Guolin Zhang,et al.  Toxicity of raw and processed roots of Polygonum multiflorum. , 2012, Fitoterapia.

[6]  Defeng Li,et al.  Network pharmacology-based identification of key pharmacological pathways of Yin–Huang–Qing–Fei capsule acting on chronic bronchitis , 2016, International journal of chronic obstructive pulmonary disease.

[7]  A. Vickers,et al.  A single arm phase II study of a Far-Eastern traditional herbal formulation (sho-sai-ko-to or xiao-chai-hu-tang) in chronic hepatitis C patients. , 2011, Journal of ethnopharmacology.

[8]  Hongcai Shang,et al.  Liver Damage Associated with Polygonum multiflorum Thunb.: A Systematic Review of Case Reports and Case Series , 2015, Evidence-based complementary and alternative medicine : eCAM.

[9]  R. Fujiwara,et al.  UDP-glucuronosyltransferase (UGT) 1A1 mainly contributes to the glucuronidation of trovafloxacin. , 2015, Drug metabolism and pharmacokinetics.

[10]  Jian Ni,et al.  Traditional usages, botany, phytochemistry, pharmacology and toxicology of Polygonum multiflorum Thunb.: A review , 2014, Journal of Ethnopharmacology.

[11]  Jong Sil Lee,et al.  Drug-Induced Liver Injury: Twenty Five Cases of Acute Hepatitis Following Ingestion of Polygonum multiflorum Thunb , 2011, Gut and liver.

[12]  Robi Tacutu,et al.  A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans , 2015, Aging cell.

[13]  Yonghua Wang,et al.  Systems pharmacology uncovers Janus functions of botanical drugs: activation of host defense system and inhibition of influenza virus replication , 2012, Integrative biology : quantitative biosciences from nano to macro.

[14]  Tsai-Chung Li,et al.  Adjunctive traditional Chinese medicine therapy improves survival of liver cancer patients , 2015, Liver international : official journal of the International Association for the Study of the Liver.

[15]  K. Tsuneyama,et al.  Toxicological role of an acyl glucuronide metabolite in diclofenac‐induced acute liver injury in mice , 2017, Journal of applied toxicology : JAT.

[16]  Marcus Schuchmann,et al.  Knockout of myeloid cell leukemia‐1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes , 2009, Hepatology.

[17]  Wei Zhou,et al.  TCMSP: a database of systems pharmacology for drug discovery from herbal medicines , 2014, Journal of Cheminformatics.

[18]  S. J. Schrieber,et al.  The Pharmacokinetics of Silymarin Is Altered in Patients with Hepatitis C Virus and Nonalcoholic Fatty Liver Disease and Correlates with Plasma Caspase-3/7 Activity , 2008, Drug Metabolism and Disposition.

[19]  S. Song,et al.  Nuclear Factor Kappa B Activation and Peroxisome Proliferator-activated Receptor Transactivational Effects of Chemical Components of the Roots of Polygonum multiflorum , 2016, Pharmacognosy magazine.

[20]  Meindert Danhof,et al.  Systems pharmacology - Towards the modeling of network interactions. , 2016, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[21]  J. Ritter,et al.  Glucuronidation of acetaminophen catalyzed by multiple rat phenol UDP-glucuronosyltransferases. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[22]  Na Li,et al.  [Study on effective substance basis and molecular mechanism of Qigui Tongfeng tablet using network pharmacology method]. , 2015, Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica.

[23]  N. Chen,et al.  First-in-class pan caspase inhibitor developed for the treatment of liver disease. , 2005, Journal of medicinal chemistry.

[24]  P. Granja,et al.  Dissecting stromal-epithelial interactions in a 3D in vitro cellularized intestinal model for permeability studies. , 2015, Biomaterials.

[25]  H. Oshio,et al.  Treatment of chronic liver injury in mice by oral administration of xiao-chai-hu-tang. , 1989, Journal of ethnopharmacology.

[26]  H. Tajiri,et al.  Effect of sho-saiko-to(xiao-chai-hu-tang) on HBeAg clearance in children with chronic hepatitis B virus infection and with sustained liver disease. , 1991, The American journal of Chinese medicine.

[27]  J. Kou,et al.  Network pharmacology-based prediction and verification of the molecular targets and pathways for schisandrin against cerebrovascular disease. , 2014, Chinese journal of natural medicines.

[28]  Xiaochao Ma,et al.  Mechanisms of Drug-Induced Hepatotoxicity. , 2017, Clinics in liver disease.

[29]  Y. Liu,et al.  Hepatoprotection and hepatotoxicity of Heshouwu, a Chinese medicinal herb: Context of the paradoxical effect. , 2017, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[30]  M. S. Abdel-Latif.  Plasma Levels of Matrix Metalloproteinase (MMP)-2, MMP-9 and Tumor Necrosis Factor-α in Chronic Hepatitis C Virus Patients , 2015, The open microbiology journal.

[31]  Zhengquan Feng,et al.  Glycyrrhizic acid inhibits apoptosis and fibrosis in carbon-tetrachloride-induced rat liver injury. , 2015, World journal of gastroenterology.

[32]  C. Xue,et al.  In silico database screening of potential targets and pathways of compounds contained in plants used for psoriasis vulgaris , 2015, Archives of Dermatological Research.

[33]  M. Yadav,et al.  A Knowledge-Based Approach for Identification of Drugs Against Vivapain-2 Protein of Plasmodium vivax Through Pharmacophore-Based Virtual Screening with Comparative Modelling , 2014, Applied Biochemistry and Biotechnology.

[34]  Tingjun Hou,et al.  ADME evaluation in drug discovery , 2002, Journal of molecular modeling.

[35]  Sheng Tian,et al.  ADME evaluation in drug discovery. 9. Prediction of oral bioavailability in humans based on molecular properties and structural fingerprints. , 2011, Molecular pharmaceutics.

[36]  S. Mastorides,et al.  Liver injury during acute pancreatitis: The role of pancreatitis-associated ascitic fluid (paaf), p38-MAPK, and caspase-3 in inducing hepatocyte apoptosis , 2003, Journal of Gastrointestinal Surgery.

[37]  D. Edwards,et al.  MMP2 activity is critical for TGFβ2-induced matrix contraction--implications for fibrosis. , 2012, Investigative ophthalmology & visual science.

[38]  M. Olivier,et al.  Genetic Variation in the Peroxisome Proliferator Activated Receptor-Gamma Gene Is Associated with Histologically Advanced NAFLD , 2012, Digestive Diseases and Sciences.

[39]  Y. Li,et al.  [Tumor necrosis factor-alpha, caspase-3 expression and hepatocyte apoptosis in fulminanting hepatic failure]. , 2003, Zhonghua nei ke za zhi.

[40]  F. Chang,et al.  Acute hepatitis induced by Chinese hepatoprotective herb, xiao-chai-hu-tang. , 2006, Journal of the Chinese Medical Association : JCMA.

[41]  Bao-Hong Lee,et al.  Hepatoprotection of emodin and Polygonum multiflorum against CCl4-induced liver injury , 2012, Pharmaceutical biology.

[42]  Li Yang,et al.  Identification of Human UDP-Glucuronosyltransferase 1A4 as the Major Isozyme Responsible for the Glucuronidation of 20(S)-Protopanaxadiol in Human Liver Microsomes , 2016, International journal of molecular sciences.

[43]  Wei Liu,et al.  A Network Pharmacology Study of Chinese Medicine QiShenYiQi to Reveal Its Underlying Multi-Compound, Multi-Target, Multi-Pathway Mode of Action , 2014, PloS one.

[44]  Guangbo Ge,et al.  Comparison of the inhibitory effects of tolcapone and entacapone against human UDP-glucuronosyltransferases. , 2016, Toxicology and applied pharmacology.

[45]  J. Li,et al.  Cobalt protoporphyrin protects the liver against apoptosis in rats of brain death. , 2015, Clinics and research in hepatology and gastroenterology.

[46]  S. Saghir.  Determination of ADME and bioavailability following intravenous, oral, and dermal routes of exposure. , 2009, Current protocols in toxicology.

[47]  A. Prat,et al.  Estrogen Signals Through Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α to Reduce Oxidative Damage Associated With Diet-Induced Fatty Liver Disease. , 2017, Gastroenterology.

[48]  N. Hiramatsu,et al.  Activation of the Mitochondrial Apoptotic Pathway Produces Reactive Oxygen Species and Oxidative Damage in Hepatocytes That Contribute to Liver Tumorigenesis , 2015, Cancer Prevention Research.