Research Progress in Triptolide-Induced Live Injury

doi:10.19803/j.1672-8629.20230658

Abstract

Abstract: Objective To summarize the research progress in the hepatotoxicity mechanism of triptolide and shed light on the mechanism of drug-induced liver injury caused by triptolide. Methods Based on literature research, the mechanism of drug induced liver injury caused by triptolide was summarized in terms of direct toxicity and indirect toxicity. Results The hepatotoxic mechanism of triptolide involved oxidative stress, mitochondrial damage, metabolic abnormalities, activation of NKT cells, imbalance between T helper cells and regulatory T cells, and increased liver sensitivity to inflammatory stimuli. Conclusion The hepatotoxicity mechanism of triptolide is complex, as there are a wide range of targets for direct toxicity. In addition, the indirect toxicity is highly concealed and complex. The elucidation of mechanisms of hepatotoxicity caused by triptolide provides a reference for enhancing the efficacy and reducing the toxicity of Tripterygium wilfordii Hook.f. and its preparations as well as for clinical safety and rational drug use.

Key words: Tripterygium wilfordii Hook.f., Triptolide, Liver Injury, Hepatotoxicity, Direct Toxicity, Indirect Toxicity, Hepatotoxicity Mechanism

CLC Number:

TANG Qianhui, ZHANG Haoran, ZHANG Luyong, JIANG Zhenzhou. Research Progress in Triptolide-Induced Live Injury[J]. Chinese Journal of Pharmacovigilance, 2025, 22(2): 121-127.

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URL: https://zgywjj.magtechjournal.com/EN/10.19803/j.1672-8629.20230658

https://zgywjj.magtechjournal.com/EN/Y2025/V22/I2/121

References

[1] REN LW, ZHEN XJ, LI W, et al.Historical Understanding and Evaluation of the Toxicity of Tripterygium Wilfordii[J]. Herald of Medicine(医药导报), 2021, 40(5): 637-641.
[2] Song CY, Xu YG, Lu YQ.Use of Tripterygium wilfordii Hook. f. for Immune-Mediated Inflammatory Diseases: Progress and Future Prospects[J]. J Zhejiang Univ Sci B, 2020, 21(4): 280-290.
[3] SONG D, GE FL, ZHANG L, et al.Analysis of Liver Injury Related to Tripterygium wilfordii Preparations[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2019, 16(5): 265-269.
[4] DING ZH, ZHANG YL, LIN N.Component-Effect/Toxicity-Target Correlations of Tripterygium Wilfordii in Terms of Lipid Metabolism[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2023, 20(5): 489-495.
[5] MA QF, ZENG T.Attention to the Safety of The Use of Tripterygium wilfordii Hook.f. Preparations[J]. Rheumatism And Arthritis(风湿病与关节炎), 2012, 1(4): 45.
[6] LIN N, JIANG Q, LIU W, et al.Guidelines for The Use of Tripterygium Wilfordii Glycosides/Tripterygium Wilfordii Tablets in the Treatment of Rheumatoid Arthritis[J]. Chinese Journal of Traditional Chinese Medicine(中国中药杂志), 2020, 45(17): 4149-4153.
[7] TIAN YG, SU XH, LIU LL, et al.Overview of Hepatotoxicity Research on Tripterygium wilfordii Hook.f. in the Past 20 Years[J]. Chinese Journal of Traditional Chinese Medicine(中国中药杂志), 2019, 44(16): 3399-3405.
[8] LI M, LUO Q, CHEN X, et al.Screening of Major Hepatotoxic Components of Tripterygium Wilfordii based on Hepatotoxic Injury Patterns[J]. BMC Complement Med Ther, 2023, 23(1): 9.
[9] BJÖRNSSON HK, BJÖRNSSON ES. Drug-Induced Liver Injury: Pathogenesis, Epidemiology, Clinical Features, and Practical Management[J]. Eur J Intern Med, 2022, 97: 26-31.
[10] HOOFNAGLE JH, BJÖRNSSON ES. Drug-Induced Liver Injury - Types and Phenotypes[J]. N Engl J Med, 2019, 381(3): 264-273.
[11] GARCIA-CORTES M, ROBLES-DIAZ M, STEPHENS C, et al.Drug induced Liver Injury: an Update[J]. Arch Toxicol, 2020, 94(10): 3381-3407.
[12] LUANGMONKONG T, SURIGUGA S, MUTSAERS HM, et al.Targeting Oxidative Stress for the Treatment of Liver Fibrosis[J]. Rev Physiol Biochem Pharmacol, 2018, 175: 71-102.
[13] FORMAN HJ, ZHANG H.Targeting Oxidative Stress in Disease: Promise and Limitations of Antioxidant Therapy[J]. Nat Rev Drug Discov, 2021, 20(9): 689-709.
[14] LI J, SHEN F, GUAN C, et al.Activation of Nrf2 Protects Against Triptolide-Induced Hepatotoxicity[J]. PLoS One, 2014, 9(7): e100685.
[15] ZHOU LL, ZHOU C, LIANG XW, et al.Self-Protection Against Triptolide-Induced Toxicity in Human Hepatic Cells Via Nrf2-ARE-NQO1 pathway[J]. Chin J Integr Med, 2017, 23(12): 929-936.
[16] HOU Z, CHEN L, FANG P, et al.Mechanisms of Triptolide-Induced Hepatotoxicity and Protective Effect of Combined Use of Isoliquiritigenin: Possible Roles of Nrf2 and Hepatic Transporters[J]. Front Pharmacol, 2018, 9: 226.
[17] FENG Z, ZHOU C, DONG S, et al.Catalpol and Panax Notoginseng Saponins Synergistically Alleviate Triptolide-Induced Hepatotoxicity Through Nrf2/ARE Pathway[J]. Toxicol in Vitro, 2019, 56: 141-149.
[18] JIANG HY, BAO YN, LIN FM, et al.Triptolide Regulates Oxidative Stress and Inflammation Leading to Hepatotoxicity via Inducing CYP2E1[J]. Hum Exp Toxicol, 2021, 40(12_suppl): S775-S787.
[19] CAO LJ, LI HD, YAN M, et al.The Protective Effects of Isoliquiritigenin and Glycyrrhetinic Acid Against Triptolide-Induced Oxidative Stress in HepG2 Cells Involve Nrf2 Activation[J]. Evid Based Complement Alternat Med, 2016, 2016: 8912184.
[20] LI S, TAN HY, WANG N, et al.The Role of Oxidative Stress and Antioxidants in Liver Diseases[J]. Int J Mol Sci, 2015, 16(11): 26087-26124.
[21] LI Y, GUO L, HOU Z, et al.Role of MicroRNA-155 in Triptolide-Induced Hepatotoxicity via the Nrf2-Dependent Pathway[J]. J Ethnopharmacol, 2021, 281: 114489.
[22] MAHMOOD DF, ABDERRAZAK A, EL HADRI K, et al.The Thioredoxin System as a Therapeutic Target in Human Health and Disease[J]. Antioxid Redox Signal, 2013, 19(11): 1266-1303.
[23] SHEN F, XIONG Z, KONG J, et al.Triptolide Impairs Thioredoxin System by Suppressing Notch1-Mediated PTEN/Akt/Txnip Signaling in Hepatocytes[J]. Toxicol Lett, 2019, 300: 105-115.
[24] MURPHY MP, HARTLEY RC.Mitochondria as a Therapeutic Target for Common Pathologies[J]. Nat Rev Drug Discov, 2018, 17(12): 865-886.
[25] BOCK FJ, TAIT SWG.Mitochondria as Multifaceted Regulators of Cell Death[J]. Nat Rev Mol Cell Biol, 2020, 21(2): 85-100.
[26] FU Q, HUANG X, SHU B, et al.Inhibition of Mitochondrial Respiratory Chain is Involved in Triptolide-Induced Liver Injury[J]. Fitoterapia, 2011, 82(8): 1241-1248.
[27] FU Q, JIANG ZZ, ZHANG LY.Impairment of Triptolide on Liver Mitochondria in Isolated Liver Mitochondria and HL7702 Cell Line[J]. Chin J Integr Med, 2013, 19(9): 683-688.
[28] HASNAT M, YUAN Z, NAVEED M, et al.Drp1-Associated Mitochondrial Dysfunction and Mitochondrial Autophagy: a Novel Mechanism in Triptolide-Induced Hepatotoxicity[J]. Cell Biol Toxicol, 2019, 35(3): 267-280.
[29] HASNAT M, YUAN Z, ULLAH A, et al.Mitochondria-Dependent Apoptosis in Triptolide-Induced Hepatotoxicity is Associated with The Drp1 Activation[J]. Toxicol Mech Methods, 2020, 30(2): 124-133.
[30] TREFTS E, GANNON M, WASSERMAN DH.The Liver[J]. Curr Biol, 2017, 27(21): R1147-R1151.
[31] BERASAIN C, ARECHEDERRA M, ARGEMÍ J, et al.Loss of Liver Function in Chronic Liver Disease: an Identity Crisis[J]. J Hepatol, 2023, 78(2): 401-414.
[32] YANG J, SUN L, WANG L, et al.Activation of Sirt1/FXR Signaling Pathway Attenuates Triptolide-Induced Hepatotoxicity in Rats[J]. Front Pharmacol, 2017, 8: 260.
[33] WANG J, JIANG Z, JI J, et al.Gene Expression Profiling and Pathway Analysis of Hepatotoxicity Induced by Triptolide in Wistar Rats[J]. Food Chem Toxicol, 2013, 58: 495-505.
[34] JIANG Z, HUANG X, HUANG S, et al.Sex-related Differences of Lipid Metabolism Induced by Triptolide: the Possible Role of the LXRα/SREBP-1 Signaling Pathway[J]. Front Pharmacol, 2016, 7: 87.
[35] LI M, HU T, TIE C, et al.Quantitative Proteomics and Targeted Fatty Acids Analysis Reveal the Damage of Triptolide in Liver and Kidney[J]. Proteomics, 2017, 17(22): 1700001.
[36] MAO YP, WEI HS.Regulation of Liver Cell Polarity[J]. Journal of Clinical Hepatology(临床肝胆病杂志), 2022, 38(11): 2654-2658.
[37] YANG T, MEI H, XU D, et al.Early Indications of ANIT-Induced Cholestatic Liver Injury: Alteration of Hepatocyte Polarization and Bile acid Homeostasis[J]. Food Chem Toxicol, 2017, 110: 1-12.
[38] HUANG S, LIU L, MEI HF, et al.Altered Integrity of Hepatocyte Tight Junctions in Rats with Triptolide-Induced Cholestasis[J]. Chin J Nat Med, 2021, 19(3): 188-194.
[39] LI C, RAO T, CHEN X, et al.HLA-B*35:01 Allele is a Potential Biomarker for Predicting Polygonum Multiflorum-Induced Liver Injury in Humans[J]. Hepatology, 2019, 70(1): 346-357.
[40] TERABE M, BERZOFSKY JA.The Immunoregulatory Role of Type I and Type II NKT cells in Cancer and Other Diseases[J]. Cancer Immunol Immunother, 2014, 63(3): 199-213.
[41] CROSBY CM, KRONENBERG M.Tissue-Specific Functions of Invariant Natural Killer T Cells[J]. Nature Reviews Immunology, 2018, 18(9): 559-574.
[42] WANG XZ, XUE RF, ZHANG SY, et al.Activation of Natural Killer T cells Contributes to Triptolide-Induced Liver Injury in Mice[J]. Acta Pharmacol Sin, 2018, 39(12): 1847-1854.
[43] ZOU M, NONG C, YU Z, et al.The Role of Invariant Natural Killer T Cells and Associated Immunoregulatory Factors in Triptolide-Induced Cholestatic Liver Injury[J]. Food Chem Toxicol, 2020, 146: 111777.
[44] CHEN X, YU Z, NONG C, et al.Activation of cDCs and iNKT Cells Contributes to Triptolide-Induced Hepatotoxicity Via STING Signaling Pathway and Endoplasmic Reticulum Stress[J]. Cell Biol Toxicol, 2022, 39(4): 1753-1772.
[45] ZHANG H, JIANG Z, ZHANG L.Dual Effect of T Helper Cell 17 (Th17) and Regulatory T Cell (Treg) in Liver Pathological Process: From Occurrence to End Stage of Disease[J]. Int Immunopharmacol, 2019, 69: 50-59.
[46] NOACK M, MIOSSEC P.Th17 and Regulatory T cell Balance in Autoimmune and Inflammatory Diseases[J]. Autoimmun Rev, 2014, 13(6): 668-677.
[47] LEE GR.The Balance of Th17 versus Treg Cells in Autoimmunity[J]. Int J Mol Sci, 2018, 19(3): 730.
[48] XU YY, WANG DM, LIANG HS, et al.The Role of Th17/Treg Axis in The Traditional Chinese Medicine Intervention on Immune-Mediated Inflammatory Diseases: a Systematic Review[J]. Am J Chin Med, 2020, 48(3): 535-558.
[49] WANG X, JIANG Z, CAO W, et al.Th17/Treg Imbalance in Triptolide-Induced Liver Injury[J]. Fitoterapia, 2014, 93: 245-251.
[50] WANG X, JIANG Z, XING M, et al.Interleukin-17 Mediates Triptolide-Induced Liver Injury in Mice[J]. Food Chem Toxicol, 2014, 71: 33-41.
[51] WANG X, SUN L, ZHANG L, et al.Effect of Adoptive Transfer or Depletion of Regulatory T Cells on Triptolide-Induced Liver Injury[J]. Front Pharmacol, 2016, 7: 99.
[52] KUBES P, JENNE C.Immune Responses in The Liver[J]. Annu Rev Immunol, 2018, 36: 247-277.
[53] KAZANKOV K, JØRGENSEN SMD, THOMSEN KL, et al. The Role of Macrophages in Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(3): 145-159.
[54] YANG X, LU D, ZHUO J, et al.The Gut-Liver Axis in Immune Remodeling: New Insight into Liver Diseases[J]. Int J Biol Sci, 2020, 16(13): 2357-2366.
[55] HEYMANN F, TACKE F.Immunology in The Liver-From Homeostasis to Disease[J]. Nat Rev Gastroenterol Hepatol, 2016, 13(2): 88-110.
[56] YUAN Z, ZHANG H, HASNAT M, et al.A New Perspective of Triptolide-Associated Hepatotoxicity: Liver Hypersensitivity Upon LPS Stimulation[J]. Toxicology, 2019, 414: 45-56.
[57] WANG L, XU D, LI L, et al.Possible Role of Hepatic Macrophage Recruitment and Activation in Triptolide-Induced Hepatotoxicity[J]. Toxicol Lett, 2018, 299: 32-39.
[58] QIN T, HASNAT M, ZHOU Y, et al.Macrophage Malfunction in Triptolide-Induced Indirect Hepatotoxicity[J]. Front Pharmacol, 2022, 13: 981996.
[59] KRENKEL O, TACKE F.Liver Macrophages in Tissue Homeostasis and Disease[J]. Nat Rev Immunol, 2017, 17(5): 306-321.
[60] LIU L, ZHANG X, XING X, et al.Triptolide Induces Liver Injury by Regulating Macrophage Recruitment and Polarization Via the Nrf2 Signaling Pathway[J]. Oxid Med Cell Longev, 2022, 2022: 1492239.
[61] SCHWABE RF, LUEDDE T.Apoptosis and Necroptosis in The Liver: a Matter of Life and Death[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(12): 738-752.
[62] BERTHELOOT D, LATZ E, FRANKLIN BS.Necroptosis, Pyroptosis and Apoptosis: an Intricate Game of cell Death[J]. Cell Mol Immunol, 2021, 18(5): 1106-1121.
[63] YUAN Z, YUAN Z, HASNAT M, et al.A New Perspective of Triptolide-Associated Hepatotoxicity: The Relevance of NF-κB and NF-κB-Mediated Cellular FLICE-Inhibitory Protein[J]. Acta Pharm Sin B, 2020, 10(5): 861-877.
[64] ZHANG H, YUAN Z, WANG J, et al.Triptolide Leads to Hepatic Intolerance to Exogenous Lipopolysaccharide and Natural-Killer-Cell Mediated Hepatocellular Damage by Inhibiting MHC class I Molecules[J]. Phytomedicine, 2023, 109: 154621.