固有型药物性肝损伤中肝实质细胞的适应性反应研究进展

doi:10.19803/j.1672-8629.20250021

摘要/Abstract

摘要： 目的归纳肝实质细胞通过适应性反应对抗固有型药物性肝损伤的研究进展,为具有潜在肝毒性的药物提供安全用药参考。方法从药物代谢模式、线粒体应激反应、肝细胞增殖方面阐述适应性反应减轻固有型药物性肝损伤的机制。结果药物导致肝损伤发生的同时将激活适应性反应,通过增加解毒代谢、降低毒性代谢、促进线粒体自噬、增强抗氧化系统、促进肝细胞增殖、调节存活肝细胞功能性基因表达等方法维持肝功能稳态,降低固有型药物性肝损伤程度。结论适应性反应机制复杂,在固有型药物性肝损伤中发挥重要的内源性保护作用。对适应性反应的研究可为有潜在肝毒性的药物提供临床安全合理用药方案和为固有型药物性肝损伤的治疗与预防提供参考。

关键词: 固有型药物性肝损伤, 适应性反应, 药物代谢酶, 线粒体应激反应, 肝再生

Abstract: Objective To summarize the research progress in the adaptive response of hepatocytes against intrinsic drug-induced liver injury so as to provide a safe medication regimen for drugs with potential hepatotoxicity. Methods By searching databases for related literature published as of January 10, 2025, the mechanism by which adaptive response of hepatocytes helped alleviate intrinsic drug-induced liver injury was studied in terms of drug metabolism, mitochondrial stress response and hepatocyte proliferation. Results Drug-induced liver injury coincided with the activation of adaptive response that was believed to maintain liver homeostasis and mitigate intrinsic drug-induced liver injury by increasing detoxification metabolism, reducing toxic metabolism, promoting mitophagia, enhancing the antioxidant system, promoting hepatocyte proliferation, and regulating functional gene expressions in surviving hepatocytes. Conclusion The mechanism of adaptive response is complex and plays an important role in endogenous protection against intrinsic drug-induced liver injury. The study of adaptive response can provide a clinically safe and rational regimen for potentially hepatotoxic drugs and facilitate the treatment and prevention of intrinsic drug-induced liver injury.

Key words: Intrinsic Drug-Induced Liver Injury, Adaptive Response, Drug Metabolizing Enzymes, Mitochondrial Stress Response, Liver Regeneration

中图分类号:

R575
R994.11

陈清钰, 江振洲, 张陆勇. 固有型药物性肝损伤中肝实质细胞的适应性反应研究进展[J]. 中国药物警戒, 2025, 22(5): 532-538.

CHEN Qingyu, JIANG Zhenzhou, ZHANG Luyong. Research Progress in Adaptive Response of Hepatocytes in Intrinsic Drug-Induced Liver Injury[J]. Chinese Journal of Pharmacovigilance, 2025, 22(5): 532-538.

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https://zgywjj.magtechjournal.com/CN/Y2025/V22/I5/532

参考文献

[1] WANG HX, DUN WL, HU JW, et al.Identification and Clinical Characteristics of Potential Suspicious Traditional Chinese Medicines in Traditional Chinese Medicine-Related Liver Injury[J]. Chinese Journal of Pharmacovigilance(中国药物警戒),2024, 21(10): 1130-1136.
[2] MA SW, LIU CH, LIU XY, et al.Chinese Guideline for Diagnosis and Management of Drug-Induced Liver Injury(2023 Version)[J]. Chinese Journal of Gastroenterology(胃肠病学), 2023, 28(7): 397-431.
[3] JIANG X, LI D, SI LQ, et al.Research Progress in Mechanisms of Idiosyncratic Drug-Induced Liver Injury Mediated by Inflammatory Stress[J]. Acta Pharmaceutica Sinica(药学学报), 2021, 56(6): 1544-1550.
[4] HE H, CHAI YY, XU YX, et al.Simultaneous Determination of Acetaminophen and Its Toxicity Related Metabolite Acetaminophen-Cysteine in Mouse Plasma by LC-MS/MS[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2023, 20(3): 266-272.
[5] ZHANG QY, Recent Clinical Advances in Drug-Induced Liver Injury[J]. Chinese Journal of Disaster Medicine(中华灾害救援医学), 2024, 11(8): 925-927, 941.
[6] ZHANG XB, YU M, LI L,et al.Research Progress on Drug-Induced Liver Injury[J]. Modern Medicine Journal of China(中国现代医药杂志), 2024, 26(1): 107-110.
[7] LIU RJ, XIN XJ.Research Advances in Pathogenesis, Risk Factors, Monitoring, and Retreatment of Drug-Induced Liver Injury[J]. Journal of Clinical Hepatology(临床肝胆病杂志), 2023, 39(4): 968-973.
[8] DU HL, LI X, SHAN XC, et al.Clinical Characteristics and Prognostic Factors of 145 Patients with Drug-Induced Liver Injury[J]. Academic Journal of Naval Medical University(海军军医大学学报), 2024, 45(10): 1259-1265.
[9] YAO KY, ZHANG SQ, JIN R, et al.Comparative Study on Data Set of Drug-Induced Liver Injury[J]. Chinese Journal of Pharmacovigil-ance(中国药物警戒), 2023, 20(5): 568-573.
[10] CHEN S, YANG CQ.Drug-Induced Liver Injury: Advances and Confusions in Treatment[J]. Journal of Clinical Hepatology(临床肝胆病杂志), 2021, 37(11): 2505-2509.
[11] REZKALLA SH, KLONER RA.Ischemic Preconditioning and Preinfarction Angina in the Clinical Arena[J]. Nature Clinical Practice Cardiovascular Medicine, 2004, 1(2): 96-102.
[12] CHU MJ, VATHER R, HICKEY AJ, et al.Impact of Ischemic Preconditioning on Outcome in Clinical Liver Surgery: a Systematic Review[J]. Biomed Research International, 2015, 2015: 370451.
[13] YANG C, ZENG MW, ZHANG WF, et al.Research Progress on the Mechanism and Protective Measures of Perioperative Hepatic Ischemia-Reperfusion Injury[J]. Journal of Regional Anatomy and Operative Surgery(局解手术学杂志), 2024, 33(4): 359-364.
[14] WU WJ, LUO GJ.Effect of Remote Ischemic Preconditioning on Clinical Prognosis of Liver Cancer Patients Undergoing Hepatectomy: a Meta-Analysis[J]. Chinese Journal of Hepatic Surgery(Electronic Edition)(中华肝脏外科手术学电子杂志), 2021, 10(3): 301-305.
[15] HAN D, DARA L, WIN S, et al.Regulation of Drug-Induced Liver Injury by Signal Transduction Pathways: Critical Role of Mitochondria[J]. Trends in Pharmacological Sciences, 2013, 34(4): 243-253.
[16] EAKINS R, WALSH J, RANDLE L, et al.Adaptation to Acetam-inophen Exposure Elicits Major Changes in Expression and Distribution of the Hepatic Proteome[J]. Scientific Reports, 2015, 5: 16423.
[17] LI JY.Effect of SiNiSan on Regulating Wnt/β-Catenin Pathway to Induce Proliferation and Differentiation of Hepatic Stem Cells in the Treatment of Liver Injury[D]. Jiangsu: Jiangsu University, 2021.
[18] FLAKS B, NICOLL JW.Modification of Toxic Liver Injury in the Rat. I. Effect of Inhibition of Protein Synthesis on the Action of 2-Acetylaminofluorene, Carbon Tetrachloride, 3'-Methyl-4-Dimethylaminoazobenzene and Diethylnitrosamine[J]. Chemico-Biological Interactions (Ireland), 1974, 8(3): 135-150.
[19] FLAKS B, NICOLL JW.Modification of Toxic Liver Injury in the Rat II. Protective Effect of Cycloheximide on Ethionine-Induced Damage and Autoprotective Effects of High Doses of Ethionine, 3'-Methyl-4-Dimethylaminoazobenzene, and 2-Acetylaminofluorene[J]. Toxicology and Applied Pharmacology, 1975, 32(3): 603-620.
[20] PHILIP BK, ANAND SS, PALKAR PS, et al.Subchronic Chloroform Priming Protects Mice from a Subsequently Administered Lethal Dose of Chloroform[J]. Toxicol Appl Pharmacol, 2006, 216(1): 108-121.
[21] SIVA VM, HENNING GE, MANAUTOU JE.Cholestasis Induced by Model Organic Anions Protects from Acetaminophen Hepatotoxicity in Male CD-1 Mice[J]. Toxicology Letters, 2006, 160(3): 204-211.
[22] ALEKSUNES LM, CAMPION SN, GOEDKEN MJ, et al.Acquired Resistance to Acetaminophen Hepatotoxicity is Associated with Induction of Multidrug Resistance-Associated Protein 4 (Mrp4) in Proliferating Hepatocytes[J]. Toxicological Sciences, 2008, 104(2): 261-273.
[23] YU L, YAN J, ZHAN Y, et al.Single-Cell RNA Sequencing Reveals the Dynamics of Hepatic Non-Parenchymal Cells in Autoprotection Against Acetaminophen-Induced Hepatotoxicity[J]. Journal of Pharmaceutical Analysis, 2023, 13(8): 926-941.
[24] RUDRAIAH S, ROHRER PR, GUREVICH I, et al.Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection Is Associated with Induction of Flavin-Containing Monooxygenase-3 (FMO3) in Hepatocytes[J]. Toxicological Sciences, 2014, 141(1): 263-277.
[25] BEN-MOSHE S, VEG T, MANCO R, et al. The Spatiotemporal Program of Zonal Liver Regeneration Following Acute Injury[J]. Cell Stem Cell, 2022, 29(6): 973-989. e10.
[26] SANCHEZ-QUANT E, RICHTER ML, COLOME-TATCHE M, et al.Single-Cell Metabolic Profiling Reveals Subgroups of Primary Human Hepatocytes with Heterogeneous Responses to Drug Challenge[J]. Genome Biology, 2023, 24(1): 234.
[27] HALPERN KB, SHENHAV R, MATCOVITCH-NTAN O, et al.Single-Cell Spatial Reconstruction Reveals Global Division of Labour in the Mammalian Liver[J]. Nature, 2017, 542(7641): 352-356.
[28] KONG L, CHEN J, JI X, et al.Alcoholic Fatty Liver Disease Inhibited the Co-Expression of Fmo5 and PPARalpha to Activate the NF-KappaB Signaling Pathway, Thereby Reducing Liver Injury via Inducing Gut Microbiota Disturbance[J]. Journal Of Experimental & Clinical Cancer Research, 2021, 40(1): 18.
[29] CASHMAN JR.Practical Aspects of Flavin-Containing Monoo-xygenase-Mediated Metabolism[J]. Chemical Research in Toxicology, 2024, 37(11): 1776-1793.
[30] O'CONNOR MA, KOZA-TAYLOR P, CAMPION SN, et al. Analysis of Changes in Hepatic Gene Expression in a Murine Model of Tolerance to Acetaminophen Hepatotoxicity (Autoprotection)[J]. Toxicology and Applied Pharmacology, 2014, 274(1): 156-167.
[31] KURAMOCHI M, IZAWA T, PERVIN M, et al.Attenuation of Thioacetamide-Induced Hepatocellular Injury by Short-Term Repeated Injections Associated with Down-Regulation of Metabolic Enzymes and Relationship with MHC Class II-Presenting Cells[J]. Experimental and Toxicologic Pathology, 2017, 69(8): 589-597.
[32] REFAT M, ZHANG G, AHMED ASA, et al.7, 8-Dihydroxy-4-Methyl Coumarin Alleviates Cholestasis via Activation of the Farnesoid X Receptor in vitro and in vivo[J]. Chemico-Biological Interactions (Ireland), 2023, 370: 110331.
[33] ACEVEDO C, BENGOCHEA L, TCHERCANSKY DM, et al.Cholestasis as a Liver Protective Factor in Paracetamol Acute Over-Dose[J]. General Pharmacology (Oxford), 1995, 26(7): 1619-1624.
[34] BENGOCHEA L, GHANEM C, PERAZZO JC, et al.Drug Glucuronidation and Hepatic Lipid Microsomal Membrane Profile in Cholestatic Rats Followed Paracetamol Intoxication[J]. Pharmaco-logical Research, 1999, 40(4): 369-376.
[35] HAO H, ZHANG L, JIANG S, et al.Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases[J]. Drug Metabolism and Disposition, 2011, 39(10): 1815-1822.
[36] WANG X, SHI LL, ZHANG YH, et al.The role of MRPs Transporters in Drug-Induced Liver Injury[J]. Chinese Journal of Pharmacovigi-lance(中国药物警戒), 2024, 21(2): 229-234.
[37] ALEKSUNES LM, SCHEFFER GL, JAKOWSKI AB, et al.Coordinated Expression of Multidrug Resistance-Associated Proteins (MRPs) in Mouse Liver during Toxicant-Induced Injury[J]. Toxico-logical Sciences, 2006, 89(2): 370-379.
[38] LI QZ, WANG MY, ZHANG SW, et al.Mitochondrial Stress and Cell Protein Homeostasis and Adaptation[J]. Progress of Anatomical Sciences(解剖科学进展), 2023, 29(5): 555-557,560.
[39] ZHENG J, YUAN Q, ZHOU C, et al.Mitochondrial Stress Response in Drug-Induced Liver Injury[J]. Molecular Biology Reports, 2021, 48(10): 6949-6958.
[40] WILLIAMS JA, DING WX.Role of Autophagy in Alcohol and Drug-Induced Liver Injury[J]. Food and Chemical Toxicology, 2020, 136: 111075.
[41] ZHANG HF, ZHOU JY, LIU ZW, et al.Huazhuojiedu Prescription is Used to Treat Ulcerative Colitis by Means of Mitochondrial Autophagy that is Mediated by PINK1-Parkin Signaling Pathway[J]. Chinese Journal of Experimental Traditional Medical Formulae(中国实验方剂学杂志), 2024, 12(19): 1-10.
[42] WANG H, NI HM, CHAO X, et al.Double Deletion of PINK1 and Parkin Impairs Hepatic Mitophagy and Exacerbates Acetaminophen-Induced Liver Injury in Mice[J]. Redox Biology, 2019, 22: 101148.
[43] XIANG YF, SUN H, CHEN Y, et al.Medication Safety and Combined Medication in Patients with Type 2 Diabetes Mellitus[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2022, 19(3): 313-316.
[44] MIAN A, BANI FAWWAZ BA, SINGH G, et al.Metformin-Induced Acute Hepatitis[J]. Cureus Journal of Medical Science, 2023, 15(5): e38908.
[45] ZHEN QF.Mechanism of Metformin Alleviates CCl₄-Inducedacute Liver Injury in Mice by Regulating Stress Response[D]. Jilin: Jilin University, 2022.
[46] LIU X, ZHAO H, LUO C, et al.Acetaminophen Responsive miR-19b Modulates SIRT1/Nrf2 Signaling Pathway in Drug-Induced Hepatotoxicity[J]. Toxicological Sciences, 2019, 170(2): 476-488.
[47] JIA ZL, CEN J, WANG JB, et al.Mechanism of Isoniazid-Induced Hepatot-oxicity in Zebrafish Larvae: Activation of ROS-Mediated ERS, Apoptosis and the Nrf2 Pathway[J]. Chemosphere, 2019, 227: 541-550.
[48] LEE EH, BAEK SY, PARK JY, et al.Rifampicin Activates AMPK and Alleviates Oxidative Stress in the Liver as Mediated with Nrf2 Signa-ling[J]. Chemico-Biological Interactions (Ireland), 2020, 315: 108889.
[49] MO YK, FAN ZH, REN F.Role of Liver Regeneration in the Repair of Liver Injury Induced by N-Acetyl-p-Aminophenol[J]. Journal of Clinical Hepatology(临床肝胆病杂志), 2024, 40(9): 1902-1907.
[50] APTE U, SINGH S, ZENG G, et al.Beta-Catenin Activation Promotes Liver Regeneration after Acetaminophen-Induced Injury[J]. American Journal of Pathology, 2009, 175(3): 1056-1065.
[51] BHUSHAN B, BORUDE P, EDWARDS G, et al.Role of Bile Acids in Liver Injury and Regeneration Following Acetaminophen Overdose[J]. American Journal of Pathology, 2013, 183(5): 1518-1526.
[52] BHUSHAN B, APTE U.The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration[J]. Cellular and Molecular Gastro-enterology and Hepatology, 2022, 13(5): 1478-1480.
[53] DALHOFF K, LAURSEN H, BANGERT K, et al.Autoprotection in Acetaminophen Intoxication in Rats: the Role of Liver Regeneration[J]. Pharmacology and Toxicology, 2001, 88(3): 135-141.
[54] WALESKY CM, KOLB KE, WINSTON CL, et al.Functional Compensation Precedes Recovery of Tissue Mass Following Acute Liver Injury[J]. Nature Communications, 2020, 11(1): 5785.
[55] SUN M, ZHAO X, LI X, et al.Aerobic Exercise Ameliorates Liver Injury in Db/Db Mice by Attenuating Oxidative Stress, Apoptosis and Inflammation through the Nrf2 and JAK2/STAT3 Signalling Pathways[J]. Journal of Inflammation Research, 2023, 16: 4805-4819.