抗结核药物所致肝损伤的分子机制

doi:10.3969/j.issn.1000-6621.2014.01.002

摘要/Abstract

摘要： 直接面视下督导化疗(DOTS)是目前结核病控制的有效策略，它主要应用4个一线抗结核药物异烟肼（INH）、利福平（RFP）、乙胺丁醇（EMB）和吡嗪酰胺（PZA）联合治疗6个月或更长时间。然而，抗结核药物不良反应尤其是INH、RFP和PZA引发的肝损伤是化疗中最常见的，联合用药时肝毒性的发生率和严重程度明显增加，给结核病的化疗带来了难题。约1.00％～30.18％的患者因为严重的肝损伤而不得不更换药物或终止治疗，少数患者甚至发生肝衰竭。抗结核药物引起肝损伤（antituberculosis drug induced live injury，ATDILI）的高发生率、严重程度和可能导致的医疗纠纷引起了广大防痨工作者对该问题的重视，但其发生的机制尚未完全阐明。因此，了解抗结核药物引起肝损伤的机制，建立快速检测方法，减少ATDILI的发生势在必行。ATDILI的发生率随着人群特点、用药方案、肝毒性诊断标准、监测和报告机制不同而有很大变化，笔者着重探讨患者遗传因素与ATDILI的相关性。

Abstract: 直接面视下督导化疗(DOTS)是目前结核病控制的有效策略，它主要应用4个一线抗结核药物异烟肼（INH）、利福平（RFP）、乙胺丁醇（EMB）和吡嗪酰胺（PZA）联合治疗6个月或更长时间。然而，抗结核药物不良反应尤其是INH、RFP和PZA引发的肝损伤是化疗中最常见的，联合用药时肝毒性的发生率和严重程度明显增加，给结核病的化疗带来了难题。约1.00％～30.18％的患者因为严重的肝损伤而不得不更换药物或终止治疗，少数患者甚至发生肝衰竭。抗结核药物引起肝损伤（antituberculosis drug induced live injury，ATDILI）的高发生率、严重程度和可能导致的医疗纠纷引起了广大防痨工作者对该问题的重视，但其发生的机制尚未完全阐明。因此，了解抗结核药物引起肝损伤的机制，建立快速检测方法，减少ATDILI的发生势在必行。ATDILI的发生率随着人群特点、用药方案、肝毒性诊断标准、监测和报告机制不同而有很大变化，笔者着重探讨患者遗传因素与ATDILI的相关性。

张俊仙，吴雪琼. 抗结核药物所致肝损伤的分子机制[J]. 中国防痨杂志, 2014, 36(1): 3-8. doi: 10.3969/j.issn.1000-6621.2014.01.002

ZHANG Jun-xian，WU Xue-qiong. The molecular mechanism of antituberculosis drug induced live injury[J]. Chinese Journal of Antituberculosis, 2014, 36(1): 3-8. doi: 10.3969/j.issn.1000-6621.2014.01.002

参考文献

［1］Shu CC, Lee CH, Lee MC, et al. Hepatotoxicity due to first-line anti-tuberculosis drugs: a five-year experience in a Taiwan medical centre. Int J Tuberc Lung Dis, 2013,17(7):934-939.
［2］房宏霞，武珊珊，吕晓珍，等.抗结核治疗期间患者出现肝损伤相关症状与肝损伤的关系分析.中国防痨杂志，2013，35（10）：816-822.
［3］黄伟，黄汉平.53例结核药致重症药物性肝炎的临床分析. 数理医药学杂志, 2004, 17(4):334.
［4］An H, Wu X, Wang Z, et al. The clinical characteristics of anti-tuberculosis drug induced liver injury in 2457 hospitalized patients with tuberculosis in China. Afr J Pharm Pharmacol, 2013, 7(13): 710-714.
［5］吴雪琼，朱冬林，张俊仙，等.羧酸酯酶基因1多态性鉴定及其与抗结核药物肝毒性相关性研究.中华内科杂志, 2012，51(7):524-530.
［6］贾忠，吴晶，马建军，等.一线抗结核药物肝损害的研究现状.中国防痨杂志，2013，35（6）：468-471.
［7］雷建平，吴雪琼，张文宏.抗结核药物所致肝损伤相关危险因素及临床处置对策.中国防痨杂志，2013，35（11）：858-864.
［8］肖和平，顾瑾.抗结核药物性肝损伤的临床特点.中国防痨杂志，2013，35（7）：485-487.
［9］Naisbitt DJ, Williams DP, Pirmohamed M, et al. Reactive metabolites and their role in drug reactions.Curr Opin Allergy Clin Immunol, 2001, 1(4):317-325.
［10］Askgaard DS, Wilcke T, Dossing M. Hepatotoxicity caused by the combined treatment action of isoniazid and rifampicin. Thorax, 1995,50(2):213-214.
［11］Sharma SK. Antituberculosis drugs and hepatotoxicity. Infect Genet Evol, 2004, 4（2）:167-170.
［12］Ellard GA, Gammon PT. Pharmacokinetics of isoniazid metabolism in man. J Pharmacokinet Biopharm,1976, 4(2):83-113.
［13］Wang PY, Xie SY, Hao Q, et al. NAT2 polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury: a meta-analysis. Int J Tuberc Lung Dis, 2012, 16(5):589-595.
［14］Higuchi N, Tahara N, Yanagihara K, et al. NAT2*6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis. World J Gastroenterol, 2007, 13(45):6003-6008.
［15］Hein DW, Doll MA, Rustan TD, et al. Metabolic activation of N-hydroxyarylamines and N-hydroxyarylamides by 16 recombinant human NAT2 allozymes: effects of 7 specific NAT2 nucleic acid substitutions. Cancer Res, 1995, 55(16):3531-3536.
［16］An HR, Wu XQ, Wang ZY, et al. NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug-induced hepatotoxicity in Chinese patients. Clin Exp Physiol,2012, 39(6):535-543.
［17］Huang YS, Chern HD, Su WJ, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology, 2002, 35(4): 883-889.
［18］Hussain Z, Kar P, Husain SA. Antituberculosis drug-induced hepatitis: risk factors, prevention and management（Review）. Indian J Exp Biol, 2003, 41(11):1226-1232.
［19］Ben Mahmoud L, Ghozzi H, Kamoun A, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis. Pathol Biol (Paris), 2012, 60(5):324-330.
［20］Chen B, Li JH, Xu YM, et al. The influence of NAT2 genotypes on the plasma concentration of isoniazid and acetylisoniazid in Chinese pulmonary tuberculosis patients. Clin Chim Acta, 2006, 365(1/2):104-108.
［21］Possuelo LG, Castelan JA, de Brito TC, et al. Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil. Eur J Clin Pharmacol, 2008, 64(7):673-681.
［22］Kim SH, Kim SH, Bahn JW, et al. Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis. Pharmacogenomics, 2009, 10(11):1767-1779.
［23］朱冬林，吴雪琼，席云，等. NAT2基因多态性与抗结核药物性肝损害的关系. 中国病原生物学杂志, 2012, 7(6):406-413.
［24］Vuilleumier N, Rossier MF, Chiappe A, et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol, 2006, 62(6):423-429.
［25］Huang YS, Chern HD, Su WJ, et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology, 2003, 37(4):924-930.
［26］Wang T, Yu HT, Wang W, et al. Genetic polymorphisms of cytochrome P450 and glutathione S-transferase associated with antituberculosis drug-induced hepatotoxicity in Chinese tuberculosis patients. J Int Med Res, 2010, 38(3):977-986.
［27］陈怡, 郭梅, 李世明, 等. 细胞色素P450 2E1基因多态性与抗结核药物致肝损伤的关系.中华传染病杂志, 2010, 28(12):748-752.
［28］Teixeira RL, Morato RG, Cabello PH, et al. Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients. Mem Inst Oswaldo Cruz, 2011, 106(6):716-724.
［29］Tang SW,Lv XZ,Zhang Y, et al. CYP2E1, GSTM1 and GSTT1 genetic polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity: a nested case-control study. J Clin Pharm Ther, 2012,37(5):588-593.
［30］Strange RC, Jones PW, Fryer AA. Glutathione S-transferase: genetics and role in toxicology(Review). Toxicol lett, 2000,(112/113):357-363.
［31］Huang YS, Su WJ, Huang YH, et al. Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H: quinine oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury. J Hepatol, 2007, 47(1):128-134.
［32］Leiro V, Fernández-Villar A, Valverde D, et al. Infuence of glutathione S-transferase M1 and T1 homozygous null mutations on the risk of antituberculosis drug-induced hepatotoxicity in a Caucasian population. Liver Int, 2008, 28(6):835-839.
［33］朱冬林，席云，吴雪琼. GSTM1和GSTT1基因多态性与抗结核药物性肝损害的关系.中国抗生素杂志，2011,36(11): 864-868.
［34］Kim SH, Kim SH, Yoon HJ, et al. GSTT1 and GSTM1 null mutations and adverse reactions induced by antituberculosis drugs in Koreans.Tuberculosis(Edinb),2010, 90(1):39-43.
［35］Shimoda-Matsubayashi S, Matsumine H, Kobayashi T, et al. Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson’s disease. Biochem Biophys Res Commun, 1996, 226 (2):561-565.
［36］安慧茹、吴雪琼、王仲元. MnSOD的基因多态性与抗结核药物性肝损害关系的研究. 中国抗生素杂志, 2012, 37(11):S1-S4.
［37］Nebert DW, Roe AL, Vandale SE, et al. NAD(P)H:quinone oxidoreductase (NQO1) polymorphism, exposure to benzene, and predisposition to disease: a HuGE review. Genet Med, 2002, 4(2):62-70.
［38］Chang JC, Liu EH, Lee CN, et al. UGT1A1 polymorphisms associated with risk of induced liver disorders by anti-tuberculosis medications. Int J Tuberc Lung Dis, 2012, 16(3):376-378.
［39］郝金奇,陈怡,李世明,等.尿苷二磷酸葡萄糖醛酸转移酶1A6基因多态性与抗结核药致肝损害的相关性.中华肝脏病杂志, 2011, 19(3):201-204.
［40］郝金奇,陈怡,李世明,等.尿苷二磷酸葡萄糖醛酸转移酶1A7基因多态性与抗结核药致肝损伤易感性的关系.中华传染病杂志, 2012, 30(3):174-178.
［41］Kim SH, Kim SH, Yoon HJ, et al. TNF-α genetic polymorphism -308G/A and antituberculosis drug-induced hepatitis. Liver Int, 2012, 32(5):809-814.
［42］Nanashima K, Mawatari T, Tahara N, et al. Genetic variants in antioxidant pathway: risk factors for hepatotoxicity in tuberculosis patients. Tuberculosis(Edinb), 2012, 92（3）:253-259.
［43］Sharma SK, Balamurugan A, Saha PK, et al. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med, 2002, 166(7):916-919.