切换至 "中华医学电子期刊资源库"

中华危重症医学杂志(电子版) ›› 2022, Vol. 15 ›› Issue (03) : 253 -257. doi: 10.3877/cma.j.issn.1674-6880.2022.03.015

综述

药物性肝损伤机制的研究进展
秦正1, 乔莉1,()   
  1. 1. 210029 南京,南京医科大学第一附属医院急诊科
  • 收稿日期:2021-03-16 出版日期:2022-06-30
  • 通信作者: 乔莉
  • 基金资助:
    国家自然科学基金项目(81772057、81571875)
  • Received:2021-03-16 Published:2022-06-30
引用本文:

秦正, 乔莉. 药物性肝损伤机制的研究进展[J]. 中华危重症医学杂志(电子版), 2022, 15(03): 253-257.

药物性肝损伤是指由各类处方或非处方的化学药物、生物制剂、传统中药、天然药、保健品、膳食补充剂及其代谢产物乃至辅料等所诱发的肝损伤[1]。肝脏是药物代谢主要的器官,易受药物及其代谢产物的影响[2]。美国、英国等西方国家中,药物性肝损伤年发病率2~3/100 000人,且是急性肝衰竭的主要原因[3,4]。中国一项由308个医学中心参与的回顾性研究发现,药物性肝损伤在中国年发生率为23.80/100 000人,远高于西方国家的报道[5]。另外,全球药物中有肝毒性者达1 100种[6]。然而药物性肝损伤发病机制复杂,缺乏特异性的诊治手段,是目前研究的热点。

1
中华医学会肝病学分会药物性肝病学组. 药物性肝损伤诊治指南[J]. 中华肝脏病杂志201523(11):810-820.
2
Garcia-Cortes M, Robles-Diaz M, Stephens C, et al. Drug induced liver injury: an update[J]. Arch Toxicol, 2020, 94 (10): 3381-3407.
3
Andrade RJ, Chalasani N, Bjornsson ES, et al. Drug-induced liver injury[J]. Nat Rev Dis Primers, 2019, 5 (1): 58.
4
Hillman L, Gottfried M, Whitsett M, et al. Clinical features and outcomes of complementary and alternative medicine induced acute liver failure and injury[J]. Am J Gastroenterol, 2016, 111 (7): 958-965.
5
Shen T, Liu Y, Shang J, et al. Incidence and etiology of drug-induced liver injury in mainland China[J]. Gastroenterology, 2019, 156 (8): 2230-2241.e11.
6
杨雪,涂荣芳,杨晋辉. 药物性肝损伤的研究进展[J]. 临床肝胆病杂志202036(3):509-513.
7
European Association for the Study of the Liver. EASL clinical practice guidelines: drug-induced liver injury[J]. J Hepatol, 2019, 70 (6): 1222-1261.
8
赖荣陶,陈成伟,于乐成. 欧洲肝病学会2019版药物性肝损伤指南值得借鉴和讨论的若干问题[J]. 中华肝脏病杂志201927(11):910-912.
9
Robles-Diaz M, Lucena MI, Kaplowitz N, et al. Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury[J]. Gastroenterology, 2014, 147 (1): 109-118.e5.
10
Tan EH, Ling ZJ, Ang PS, et al. Comparison of laboratory threshold criteria in drug-induced liver injury detection algorithms for use in pharmacovigilance[J]. Pharmacoepidemiol Drug Saf, 2020, 29 (11): 1480-1488.
11
Ibrahim S, Dayoub R, Krautbauer S, et al. Bile acid-induced apoptosis and bile acid synthesis are reduced by over-expression of Augmenter of Liver Regeneration (ALR) in a STAT3-dependent mechanism[J]. Exp Cell Res, 2019, 374 (1): 189-197.
12
Norman BH. Drug induced liver injury (DILI). Mechanisms and medicinal chemistry avoidance/mitigation strategies[J]. J Med Chem, 2020, 63 (20): 11397-11419.
13
耿文静,刘晖,丁惠国. 药物性肝损伤的潜在机制、病理特点及生物标志物[J]. 临床肝胆病杂志201935(4):925-929.
14
Aleo MD, Luo Y, Swiss R, et al. Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump[J]. Hepatology, 2014, 60 (3): 1015-1022.
15
Watkins PB. The DILI-sim initiative: insights into hepatotoxicity mechanisms and biomarker interpretation[J]. Clin Transl Sci, 2019, 12 (2): 122-129.
16
Uetrecht J. Mechanistic studies of idiosyncratic DILI: clinical implications[J]. Front Pharmacol, 2019 (10): 837.
17
Ye H, Nelson LJ, Gómez Del Moral M, et al. Dissecting the molecular pathophysiology of drug-induced liver injury[J]. World J Gastroenterol, 2018, 24 (13): 1373-1385.
18
Cichoz-Lach H, Michalak A. Oxidative stress as a crucial factor in liver diseases[J]. World J Gastroenterol, 2014, 20 (25): 8082-8091.
19
杨婷婷,江振洲,张陆勇. 经由线粒体损伤诱发的药源性肝损伤研究进展[J]. 药学进展201438(11):809-818.
20
Chan JCY, Soh ACK, Kioh DYQ, et al. Reactive metabolite-induced protein glutathionylation: a potentially novel mechanism underlying acetaminophen hepatotoxicity[J]. Mol Cell Proteomics, 2018, 17 (10): 2034-2050.
21
Wang Q, Wei S, Zhou H, et al. Hyperglycemia exacerbates acetaminophen-induced acute liver injury by promoting liver-resident macrophage proinflammatory response via AMPK/PI3K/AKT-mediated oxidative stress[J]. Cell Death Discov, 2019 (5): 119.
22
Lv H, Zhu C, Wei W, et al. Enhanced Keap1-Nrf2/ Trx-1 axis by daphnetin protects against oxidative stress-driven hepatotoxicity via inhibiting ASK1/JNK and Txnip/NLRP3 inflammasome activation[J]. Phytomedicine, 2020 (71): 153241.
23
Shang XY, Chen JJ, Song XY, et al. Daphnegiravone D from Daphne giraldii Nitsche induces p38-dependent apoptosis via oxidative and nitrosative stress in hepatocellular carcinoma cells[J]. Biomed Pharmacother, 2018 (107): 1426-1433.
24
Fouad AA, Hafez HM, Hamouda A. Hydrogen sulfide modulates IL-6/STAT3 pathway and inhibits oxidative stress, inflammation, and apoptosis in rat model of methotrexate hepatotoxicity[J]. Hum Exp Toxicol, 2020, 39 (1): 77-85.
25
McMillian M, Nie A, Parker JB, et al. Drug-induced oxidative stress in rat liver from a toxicogenomics perspective[J]. Toxicol Appl Pharmacol, 2005, 207 (2 Suppl): 171-178.
26
Song L, Zhang ZR, Zhang JL, et al. MicroRNA-122 is involved in oxidative stress in isoniazid-induced liver injury in mice[J]. Genet Mol Res, 2015, 14 (4): 13258-13265.
27
任彩瑗,任锋. 外泌体在肝脏疾病中的作用研究[J/CD]. 中华危重症医学杂志(电子版)201710(4):279-283.
28
Feng S, He X. Mechanism-based inhibition of CYP-450: an indicator of drug-induced hepatotoxicity[J]. Curr Drug Metab, 2013, 14 (9): 921-945.
29
Iorga A, Dara L, Kaplowitz N. Drug-induced liver injury: cascade of events leading to cell death, apoptosis or necrosis[J]. Int J Mol Sci, 2017, 18 (5): 1018.
30
Fromenty B. Alteration of mitochondrial DNA homeostasis in drug-induced liver injury[J]. Food Chem Toxicol, 2020 (135): 110916.
31
Tirmenstein MA, Hu CX, Gales TL, et al. Effects of troglitazone on HepG2 viability and mitochondrial function[J]. Toxicol Sci, 2002, 69 (1): 131-138.
32
Shirakawa M, Sekine S, Tanaka A, et al. Metabolic activation of hepatotoxic drug (benzbromarone) induced mitochondrial membrane permeability transition[J]. Toxicol Appl Pharmacol, 2015, 288 (1): 12-18.
33
Syed M, Skonberg C, Hansen SH. Mitochondrial toxicity of diclofenac and its metabolites via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria: possible role in drug induced liver injury (DILI)[J]. Toxicol In Vitro, 2016 (31): 93-102.
34
Satapathy SK, Kuwajima V, Nadelson J, et al. Drug-induced fatty liver disease: an overview of pathogenesis and management[J]. Ann Hepatol, 2015, 14 (6): 789-806.
35
Han D, Dara L, Win S, et al. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria[J]. Trends Pharmacol Sci, 2013, 34 (4): 243-253.
36
Xie Y, Ramachandran A, Breckenridge DG, et al. Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury[J]. Toxicol Appl Pharmacol, 2015, 286 (1): 1-9.
37
Lee SK, Bae GH, Kim YS, et al. A phospholipase D2 inhibitor, CAY10594, ameliorates acetaminophen-induced acute liver injury by regulating the phosphorylated-GSK-3β/JNK axis[J]. Sci Rep, 2019, 9 (1): 7242.
38
Lee DH, Jung YS, Yun J, et al. Peroxiredoxin 6 mediates acetaminophen-induced hepatocyte death through JNK activation[J]. Redox Biol, 2020 (32): 101496.
39
Li L, Wang H, Zhang J, et al. SPHK1 deficiency protects mice from acetaminophen-induced ER stress and mitochondrial permeability transition[J]. Cell Death Differ, 2020, 27 (6): 1924-1937.
40
Li W, Yang GL, Zhu Q, et al. TLR4 promotes liver inflammation by activating the JNK pathway[J]. Eur Rev Med Pharmacol Sci, 2019, 23 (17): 7655-7662.
41
Win S, Than TA, Zhang J, et al. New insights into the role and mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases[J]. Hepatology, 2018, 67 (5): 2013-2024.
42
Li M, Cai SY, Boyer JL. Mechanisms of bile acid mediated inflammation in the liver[J]. Mol Aspects Med, 2017 (56): 45-53.
43
Schadt HS, Wolf A, Pognan F, et al. Bile acids in drug induced liver injury: key players and surrogate markers[J]. Clin Res Hepatol Gastroenterol, 2016, 40 (3): 257-266.
44
厉文,袁芳,王来友. 药物性胆汁淤积发生机制与防治研究进展[J]. 世界华人消化杂志201927(21):1295-1303.
45
Stieger B. Role of the bile salt export pump, BSEP, in acquired forms of cholestasis[J]. Drug Metab Rev, 2010, 42 (3): 437-445.
46
Qiu X, Zhang Y, Liu T, et al. Disruption of BSEP function in HepaRG cells alters bile acid disposition and is a susceptive factor to drug-induced cholestatic injury[J]. Mol Pharm, 2016, 13 (4): 1206-1216.
47
Chan R, Benet LZ. Measures of BSEP inhibition in vitro are not useful predictors of DILI[J]. Toxicol Sci, 2018, 162 (2): 499-508.
48
叶立红,郑欢伟,黄肖雨,等. 3种跨膜转运蛋白在胆管细胞损伤型药物性肝损伤患者肝组织中的表达特点及意义[J]. 临床肝胆病杂志202036(7):1562-1566.
49
Beaudoin JJ, Bezencon J, Sjostedt N, et al. Role of organic solute transporter alpha/beta in hepatotoxic bile acid transport and drug interactions[J]. Toxicol Sci, 2020, 176 (1): 34-35.
50
Slizgi JR, Lu Y, Brouwer KR, et al. Inhibition of human hepatic bile acid transporters by tolvaptan and metabolites: contributing factors to drug-induced liver injury?[J]. Toxicol Sci, 2016, 149 (1): 237-250.
51
Ju C, Reilly T. Role of immune reactions in drug-induced liver injury (DILI)[J]. Drug Metab Rev, 2012, 44 (1): 107-115.
52
De Martin E, Michot JM, Papouin B, et al. Cha-racterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors[J]. J Hepatol, 2018, 68 (6): 1181-1190.
53
Metushi I, Uetrecht J, Phillips E. Mechanism of isoniazid-induced hepatotoxicity: then and now[J]. Br J Clin Pharmacol, 2016, 81 (6): 1030-1036.
54
Hoofnagle JH, Bjornsson ES. Drug-induced liver injury-types and phenotypes[J]. N Engl J Med, 2019, 381 (3): 264-273.
55
Wuillemin N, Adam J, Fontana S, et al. HLA haplotype determines hapten or p-i T cell reactivity to flucloxacillin[J]. J Immunol, 2013, 190 (10): 4956-4964.
56
Uetrecht J, Kaplowitz N. Inhibition of immune tolerance unmasks drug-induced allergic hepatitis[J]. Hepatology, 2015, 62 (2): 346-348.
57
Roth RA, Maiuri AR, Ganey PE. Idiosyncratic drug-induced liver injury: is drug-cytokine interaction the linchpin?[J]. J Pharmacol Exp Ther, 2017, 360 (2): 461-470.
58
徐丹丹,崔大伟,邓永乐,等. 基于大数据驱动的临床用血全程闭环智能信息化管理路径构建及其应用[J/CD]. 中华危重症医学杂志(电子版)202013(5):373-375.
59
茅益民. 加强转化研究 促进药物性肝损伤的科学监管[J]. 药物不良反应杂志202022(2):58-61.
No related articles found!
阅读次数
全文


摘要