药源性肝损伤潜在血清生物标志物的研究进展

doi:10.3969/j.issn.1006-7795.2014.04.026

摘要/Abstract

摘要：

近年来，生物标志物的研究已成为药物临床前安全性评价中发展最快的领域。在药物的使用过程中，机体受药物或其代谢产物的毒性作用，或过敏反应而引发肝损伤。传统的肝损伤诊断指标主要依靠血清肝功能检测（如丙氨酸氨基转移酶、门冬氨酸氨基转移酶、碱性磷酸酶等），但这些传统指标在特异性和敏感性方面都存在一定的局限性。近几年，对肝损伤相关的新的潜在生物标志物，如微小RNA-122、α-谷胱甘肽-S转移酶、对氧磷酶、嘌呤核苷磷酸化酶、苹果酸脱氢酶、T-激肽原等的研究越来越多。本文对近期国内外较新的药源性肝损伤的血清生物标志物进行简述。

关键词: 生物标志物, 肝损伤, 药源性

Abstract:

In the recent years, the research about biomarkers of drug-induced liver injury is a rapid development area in drugs' preclinical safety evaluation and assessment. During the process of taking drugs, the organism received toxicities of drugs and/or its metabolites, or anaphylaxis to lead to liver injury. The traditional biomarkers for assessing liver injury is based primarily on the detection of hepatic enzymes in blood, such as alanine aminotransferase(ALT), aspartate aminotransferase(AST), alkaline phosphate(ALP) et al. However, elevation of blood hepatic enzymes has limitations in specificity and sensitivity. Recently, there are many results about the candidate serum biomarkers of liver injury have been reported, such as miRNA-122, α-glutathione-S-transferase(α-GST), paraoxonase(PON-1), purine nucleoside phosphorylase(PNP), malate dehydrogenase(MDH), thiostatin et al. This review was designed to assess the value of potential biomarkers for improving the detection of liver injury.

Key words: biomarkers, hepatotoxicity, drug-induced liver injury

中图分类号:

刘晓娜, 刘密凤, 贾栗, 彭双清. 药源性肝损伤潜在血清生物标志物的研究进展[J]. 首都医科大学学报, 2014, 35(4): 511-515.

Liu Xiaona, Liu Mifeng, Jia Li, Peng Shuangqing. Progress in potential candidate serum biomarker of drug-induced liver injury[J]. Journal of Capital Medical University, 2014, 35(4): 511-515.

参考文献

[1] Corsini A, Bortolini M. Drug-induced liver injury: the role of drug metabolism and transport[J]. J Clin Pharmacol, 2013,53(5):463-474.
[2] Hawkins M T, Lewis J H. Latest advances in predicting DILI in human subjects: focus on biomarkers[J]. Expert Opin Drug Metab Toxicol, 2012,8(12):1521-1530.
[3] Adler M, Hoffmann D, Ellinger-Ziegelbauer H, et al. Assessment of candidate biomarkers of drug-induced hepatobiliary injury in preclinical toxicity studies[J]. Toxicol Lett, 2010,196(1):1-11.
[4] Amacher D E, Schomaker S J, Aubrecht J, et al. Development of blood biomarkers for drug-induced liver injury: an evaluation of their potential for risk assessment and diagnostics[J]. Mol Diagn Ther, 2013,17(6):343-354.
[5] Bartel D P. MicroRNAs: genomics, biogenesis, mechanism, and function[J]. Cell, 2004,116(2):281-297.
[6] Chen X, Ba Y, Ma L, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases[J]. Cell Res, 2008,18(10):997-1006.
[7] Starkey Lewis P J, Merz M, Couttet P, et al. Serum microRNA biomarkers for drug-induced liver injury[J]. Clin Pharmacol Ther, 2012,92(3):291-293.
[8] Bala S, Petrasek J, Mundkur S, et al. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases[J]. Hepatology, 2012,56(5):1946-1957.
[9] Lawrie C H, Gal S, Dunlop H M, et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma[J]. Br J Haematol, 2008,141(5):672-675.
[10] Bala S, Marcos M, Szabo G, et al. Emerging role of microRNAs in liver diseases[J]. World J Gastroenterol, 2009,15(45):5633-5640.
[11] Starkey Lewis P J, Dear J, Platt V, et al. Circulating microRNAs as potential markers of human drug-induced liver injury[J]. Hepatology, 2011,54(5):1767-1776.
[12] Zhang Y, Jia Y, Zheng R, et al. Plasma microRNA-122 as a biomarker for viral-, alcohol-, and chemical-related hepatic diseases[J]. Clin Chem, 2010,56(12):1830-1838.
[13] Yamaura Y, Nakajima M, Takagi S, et al. Plasma microRNA profiles in rat models of hepatocellular injury, cholestasis, and steatosis[J]. PLoS One, 2012,7(2):e30250.
[14] Lagos-Quintana M, Rauhut R, Yalcin A, et al. Identification of tissue-specific microRNAs from mouse[J]. Curr Biol, 2002,12(9):735-739.
[15] Laudadio I, Manfroid I, Achouri Y, et al. A feedback loop between the liver-enriched transcription factor network and miR-122 controls hepatocyte differentiation[J]. Gastroenterology, 2012,142(1):119-129.
[16] Esau C, Davis S, Murray S F, et al. MiR-122 regulation of lipid metabolism revealed by in vivo antisense targeting[J]. Cell Meta, 2006,3(2):87-98.
[17] Krützfeldt J, Rajewsky N, Braich R, et al. Silencing of microRNAs in vivo with 'antagomirs'[J]. Nature, 2005,438(7068):685-689.
[18] Su Y W, Chen X, Jiang Z Z, et al. A panel of serum microRNAs as specific biomarkers for diagnosis of compound-and herb-induced liver injury in rats[J]. PLoS ONE, 2012,7(5):e37395.
[19] 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.
[20] Wang K, Zhang S, Marzolf B, et al. Circulating microRNAs, potential biomarkers for drug-induced liver injury[J]. Proc Nat Acad Sci U S A, 2009,106(11):4402-4407.
[21] Gui J, Tian Y, Wen X, et al. Serum microRNA characterization identifies miR-885-5p as a potential marker for detecting liver pathologies[J]. Clin Sci(Lond), 2011,120(5):183-193.
[22] Roth C, Rack B, Müller V, et al. Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer[J]. Breast Cancer Res, 2010,12(6):R90.
[23] Zheng D, Haddadin S, Wang Y, et al. Plasma microRNAs as novel biomarkers for early detection of lung cancer[J]. Int J Clin Exp Pathol, 2011,4(6):575-586.
[24] Shi Q, Yang X, Mendrick D L, et al. Hopes and challenges in using miRNAs as translational biomarkers for drug-induced liver injury[J]. Biomark Med, 2013,7(2):307-315.
[25] 乔靖怡,周璐,金若敏,等.四氯化碳致大鼠肝损伤早期血清总胆汁酸,α-谷胱甘肽S转移酶,嘌呤核苷磷酸化酶和鸟氨酸氨基甲酰转移酶的变化[J].中国药理学与毒理学杂志,2013,27(4):650-656.
[26] 任会明,李春海,谭子兴,等.人肝碱性谷胱甘肽S-转移酶与肝细胞损伤性疾病关系的初步研究[J].中华实验和临床病毒学杂志,1997,11(3):232-236.
[27] Müller C, Dünschede F, Koch E, et al. Alpha-lipoic acid preconditioning reduces ischemia-reperfusion injury of the rat liver via the PI3-kinase/Akt pathway[J]. Am J Physiol Gastroint Liver Physiol, 2003,285(4):G769-G778.
[28] 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.
[29] 陈芊伊,吕星,张志杰,等.肝硬化患者血清苹果酸脱氢酶的活性检测[J].临床和实验医学杂志,2011,10(5):347-349.
[30] Shi Q, Hong H, Senior J, et al. Biomarkers for drug-induced liver injury[J]. Expert Rev Gastroenterol Hepatol, 2010,4(2):225-234.
[31] O'Brien P J, Slaughter M R, Polley S R, et al. Advantages of glutamate dehydrogenase as a blood biomarker of acute hepatic injury in rats[J]. Lab Anim, 2002,36(3):313-321.
[32] Zhang Y, Lu N H, Gao Z H, et al. Hemin-H₂O₂-NO₂-induced protein oxidation and tyrosine nitration are different from those of SIN-1: A study on glutamate dehydrogenase nitrative/oxidative modification[J]. Int J Biochem Cell Biol, 2009,41(4):907-915.
[33] Bandara L R, Kelly M D, Lock E A, et al. A correlation between a proteomic evaluation and conventional measurements in the assessment of renal proximal tubular toxicity[J]. Toxicol Sci, 2003,73(1):195-206.
[34] Ferré N, Marsillach J, Camps J, et al. Paraoxonase-1 is associated with oxidative stress, fibrosis and FAS expression in chronic liver diseases[J]. J Hepatol. 2006,45(1):51-59.
[35] Abraham P, Sugumar E. Increased glutathione levels and activity of PON1(phenyl acetate esterase) in the liver of rats after a single dose of cyclophosphamide: A defense mechanism?[J]. Exp Toxicol Pathol, 2008,59(5):301-306.
[36] Bell L N, Vuppalanchi R, Watkins P B, et al. Serum proteomic profiling in patients with drug-induced liver injury[J]. Aliment Pharmacol Ther, 2012,35(5):600-612.