药物性肝损伤相关生物学标志物的研究进展

郭佩; 卢旺; 杨文轩; 胡玉琳

doi:10.3969/j.issn.1001-5256.2016.09.043

药物性肝损伤相关生物学标志物的研究进展

DOI: 10.3969/j.issn.1001-5256.2016.09.043

1. 吉林大学白求恩第一医院肝胆胰内科
2. 厦门大学附属第一医院急诊部
3. 泰安市中心医院超声科

详细信息

中图分类号: R575
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出版历程
- 出版日期: 2016-09-20

Research progress in biomarkers of drug-induced liver injury

Department of Hepatology, The First Hospital of Jilin University

摘要

摘要:
药物性肝损伤(DILI)是导致上市药物撤市和药物临床试验失败的主要原因之一。潜在肝损伤的检测对临床管理及临床前药物安全研究是一个挑战。目前,ALT、AST是评估肝损伤的金标准。然而,这些评估指标特异性差且不敏感,经常导致假阳性。因此,人们一直致力于寻找敏感性、特异性高的DILI相关生物学标志物。综述了近期DILI相关生物学标志物的研究进展,以便更好地预测、诊断DILI。
- 药物性肝损伤 /
- 生物学标记 /
- 综述
Abstract:
Drug- induced liver injury( DILI) is a major reason for the recall of marketed drugs and the failure of clinical trials. Detection of potential liver injury remains a challenge for clinical management and preclinical drug safety studies. Currently,serum levels of alanine aminotransferase and aspartate aminotransferase are the gold standards for evaluating liver injury. However,these biomarkers are nonspecific and insensitive,and often result in false- positive results. Therefore,researchers have never stopped searching for the biomarkers of DILI with high sensitivity and specificity. This review summarizes recent research progress in the biomarkers of DILI to better predict and diagnose DILI.
- drug-induced liver injury /
- biological markers /
- review

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参考文献(33)

[1]Drug-induced Liver Disease Study Group,Chinese Society of Hepatology,Chinese Medical Association.Guidelines for the management of drug-induced liver injury[J].J Clin Hepatol,2015,31(11):1752-1769.(in Chinese)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].临床肝胆病杂志,2015,31(11):1752-1769.

[2]THULIN P,NORDAHL G,GRY M,et al.Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts[J].Liver Int,2014,34(3):367-378.

[3]LAWRIE CH,GAL S,DUNLOP HM,et al.Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma[J].Brit J Haematol,2008,141(5):672-675.

[4]LI LM,WANG D,ZEN K,et al.MicroRNAs in drug-induced liver injury[J].J Clin Transl Hepatol,2014,2(3):162-169.

[5]STARKEY LEWIS PJ,DEAR J,PLATT V,et al.Circulating microRNAs as potential markers of human drug-induced liver injury[J].Hepatology,2011,54(5):1767-1776.

[6]YANG X,GREENHAW J,SHI Q,et al.Identification of urinary microRNA profiles in rats that may diagnose hepatotoxicity[J].Toxicol Sci,2012,125(2):335-344.

[7]VLIEGENTHART AD,ANTOINE DJ,DEAR JW,et al.Target biomarker profile for the clinical management of paracetamol overdose[J].Br J Clin Pharmacol,2015,80(3):351-362.

[8]ANTOINE DJ,JENKINS RE,DEAR JW,et al.Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity[J].J Hepatol,2012,56(5):1070-1079.

[9]CRAIG DG,LEE P,PRYDE EA,et al.Circulating apoptotic and necrotic cell death markers inpatients with acute liver injury[J].Liver Int,2011,31(8):1127-1136.

[10]ANTOINE DJ,WILLIAMS DP,KIPAR A,et al.High Mobility Group Box-1 protein and Keratin-18,circulating serum proteins informative of acetaminophen-induced necrosis and apoptosis in vivo[J].Toxicol Sci,2009,112(2):521-531.

[11]LOTZE MT,TRACEY KJ.High-mobility group box 1 protein(HMGB1):nuclear weapon in the immune arsenal[J].Nat Rev Immunol,2005,5(4):331-342.

[12]BONALDI T,TALAMO F,SCAFFIDI P,et al.Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion[J].Embo J,2003,22(20):5551-5560.

[13]ANTOINE DJ,DEAR JW,LEWIS PS,et al.Mechanistic biomarkers provide early and sensitive detection of acetaminophen‐induced acute liver injury at first presentation to hospital[J].Hepatology,2013,58(2):777-787

[14]RUHL CE,EVERHART JE.Relation of elevated serum alanine aminotransferase activity with iron and antioxidant levels in the United States[J].Gastroenterology,2003,124(7):1821-1829.

[15]YANG RZ,PARK S,REAGAN WJ,et al.Alanine aminotransferase isoenzymes:molecular cloning and quantitative analysis of tissue expression in rats and serum elevation in liver toxicity[J].Hepatology,2009,49(2):598-607.

[16]LEE WK,SHIN S,CHO SS,et al.Purification and characterization of glutamate dehydrogenase as anotherisoprotein binding to the membrane of rough endoplasmic reticulum[J].J Cell Biochem,1999,76(2):244-253.

[17]MCGILL MR,STAGGS VS,SHARPE MR,et al.Serum mitochondrial biomarkers and damage-associated molecular patterns are higher in acetaminophen overdose patients with poor outcome[J].Hepatology,2014,60(4):1336-1345.

[18]MCGILL MR,SHARPE MR,WILLIAMS CD,et al.The mechanism underlying acetaminopheninduced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation[J].Clin Invest,2012,122(4):1574-1583.

[19]SHI Q,YANG X,MATTES WB.Circulating mitochondrial biomarkers for drug-induced liver injury[J].Biomark Med,2015,9(11):1215-1223.

[20]TEGERIS AS,SMALLEY HE Jr,EARL FL,et al.Ornithine carbamyl transferase as a liver function test comparative studies in the dog,swine,and man[J].Toxicol Appl Pharmacol,1969,14(1):54-66.

[21]BONDY GS,ARMSTRONG CL,CURRAN IH,et al.Retrospective evaluation of serum ornithine carbamyltransferase activity as an index of hepatotoxicity in toxicological studies with rats[J].Toxicol Lett,2000,114(1-3):163-171.

[22]HU Z,LAUSTED C,YOO H,et al.Quantitative liver-specific protein fingerprint in blood:a signature for hepatotoxicity[J].Theranostics,2014,4(2):215-228.

[23]WEERASINGHE SV,JANG YJ,FONTANA RJ,et al.Carbamoyl phosphate synthetase-1 is a rapid turnover biomarker in mouse and human acute liver injury[J].Am J Physiol Gastrointest Liver Physiol,2014,307(3):g355-g364.

[24]MILLER TJ,KNAPTON A,ADEYEMO O,et al.Cytochrome c:a non-invasive biomarker of drug-induced liver injury[J].J Appl Toxicol,2008,28(7):815-828.

[25]KOBAYASHI Y,MORI M,NAURTO T,et al.Dynamic movement of cytochrome c from mitochondria into cytosol and peripheral circulation in massive hepatic cell injury[J].Pediat Int,2004,46(6):685-692.

[26]AMACHER DE,ADLER R,HERATH A,et al.Use of proteomic methods to identify serum biomarkers associated with rat liver toxicity or hypertrophy[J].Clin Chem,2005,51(10):1796-1803.

[27]SCHOMAKER S,WARNER R,BOCK J,et al.Assessment of emerging biomarkers of liver injury in human subjects[J].Toxicol Sci,2013,132(2):276-283.

[28]OZER J,RATNER M,SHAW M,et al.The current state of serum biomarkers of hepatotoxicity[J].Toxicology,2008,245(3):194-205.

[29]GAO H,LI N,WANG JY,et al.Definitive diagnosis of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids[J].J Dig Dis,2012,13(1):33-39.

[30]LIN G,WANG JY,LI N,et al.Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum[J].J Hepatol,2011,54(4):666-673.

[31]PENG SS,CUI YY,KONG WL,et al.Hepaticveno-occlusive disease induced by Gynurasegetum:a report of two cases[J].J Clin Hepatol,2015,31(7):1132-1134.(in Chinese)彭姗姗,崔园园,孔文丽,等.土三七致肝小静脉闭塞症2例报告[J].临床肝胆病杂志,2015,31(7):1132-1134.

[32]ODA S,MATSUO K,NAKAJIMA A,et al.A novel cell-based assay for the evaluation of immune-and inflammatory-related gene expression as biomarkers for the risk assessment of drug-induced liver injury[J].Toxicol Lett,2016,241:60-70.

[33]SAITO Y,KPDAMA S,SUGIYAMA E,et al.Predictive genomic markers for severe adverse drug reactions[J].Yakugaku Zasshi,2015,135(4):589-595.

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