异烟肼致肝损伤发病机制的研究进展
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摘要
异烟肼(isoniazid,INH)是化学预防、治疗结核病的重要药物之一,是四大一线抗结核病药物中至关重要的首选药物。一系列研究表明异烟肼具有肝脏毒性,而其肝损伤机制仍未阐明。对异烟肼肝毒性与其代谢物、线粒体功能障碍、氧化应激、脂质过氧化的关系进行阐述。综述现阶段潜在的异烟肼肝毒性机制研究,为后续深入揭示该方面研究工作提供参考。
Isoniazid(INH) is one of the most important drugs for the prevention and treatment of tuberculosis,and is the first choice for the four major first-line anti-tuberculosis drugs.A series of studies have shown that isoniazid has hepatotoxicity,and the mechanism of liver injury remains unclear.The relationship between hepatotoxicity of isoniazid and its metabolites,mitochondrial dysfunction,oxidative stress and lipid peroxidation were described in this paper.Mechanism of isoniazid on hepatotoxicity at the current stage was reviewed,and the research progress was summarized,which provided reference for further revealing the mechanism of hepatotoxicity of isoniazid.
Isoniazid(INH) is one of the most important drugs for the prevention and treatment of tuberculosis,and is the first choice for the four major first-line anti-tuberculosis drugs.A series of studies have shown that isoniazid has hepatotoxicity,and the mechanism of liver injury remains unclear.The relationship between hepatotoxicity of isoniazid and its metabolites,mitochondrial dysfunction,oxidative stress and lipid peroxidation were described in this paper.Mechanism of isoniazid on hepatotoxicity at the current stage was reviewed,and the research progress was summarized,which provided reference for further revealing the mechanism of hepatotoxicity of isoniazid.
引文
[1] RAMAPPA V,AITHAL G P.Hepatotoxicity related to anti-tuberculosis drugs:mechanisms and management[J].J Clin Exp Hepatol,2013,3(1):37-49.
[2] Williams C.Global tuberculosis control:WHO report 2011[J].Austral New Zeal J Publ Health,2012,36(5):497-498.
[3] DEVARBHAVI H,DIERKHISING R,KREMERS W K.Antituberculosis therapy drug-induced liver injury and acute liver failure[J].Hepatology,2010,52(2):798-799.
[4] PARK W B,KIM W,LEE K L,et al.Antituberculosis drug-induced liver injury in chronic hepatitis and cirrhosis[J].J Infect,2010,61(4):323-329.
[5] YEW WW,LEUNG C C.Antituberculosis drugs and hepatotoxicity[J].Am J Respir Crit Care Med,2007,175(8):858.
[6] WANG P C,PRADHAN K,ZHONG X B,et al.Isoniazid metabolism and hepatotoxicity[J].Acta Pharm Sin B,2016,6(5):384-392.
[7] METUSHI I G,CAI P,ZHU X,et al.A fresh look at the mechanism of isoniazid-induced hepatotoxicity[J].Clin Pharmacol Ther,2011,89(6):911-914.
[8] MITCHELL J R,ZIMMERMAN H J,ISHAK K G,et al.Isoniazid liver injury:clinical spectrum,pathology,and probable pathogenesis[J].Ann Intern Med,1976,84(2):181-192.
[9] INGAWALE D K,MANDLIK S K,NAIK S R.Models ofhepatotoxicity and the underlying cellular,biochemical and immunological mechanism(s):A critical discussion[J].Environ Toxicol Pharmacol,2014,37(1):118-133.
[10] HASSAN H M,HONGLI G,YOUSEF B A,et al.Hepatotoxicity mechanisms of isoniazid:A mini-review[J].J Appl Toxicol,2015,35(12):1427-1432.
[11] BALó J.Role of hydrazine incarcinogenesis[J].Adv Cancer Res,1979,30:151-164.
[12] TIMPERIO A M,RINALDUCCI S,ZOLLA L.Hydrazide derivatives produce active oxygen species as hydrazine[J].Bioorg Chem,2005,33(6):459-469.
[13] PERWITASARI D A,ATTHOBARI J,WILFFERT B.Pharmacogenetics of isoniazid-induced hepatotoxicity[J].Drug Metab Rev,2015,47(2):222-228.
[14] GARROD S,BOLLARD M E,NICHOLLS A W,et al.Integrated metabonomic analysis of the multiorgan effects of hydrazine toxicity in the rat[J].Chem Res Toxicol,2005,18(2):115-122.
[15] BANDO K,KUNIMATSU T,JUN S K,et al.GC-MS-based metabolomics reveals mechanism of action for hydrazine induced hepatotoxicity in rats[J].J Appl Toxicol,2011,31(6):524-535.
[16] OLTHOF E,TOSTMANN A,PETERS W H,et al.Hydrazine-induced liver toxicity is enhanced by glutathione depletion but is not mediated by oxidative stress in HepG2 cells[J].Int J Antimicrob Agents,2009,34(4):385-386.
[17] BOELSTERLI U A,LEE KK.Mechanisms of isoniazid-induced idiosyncratic liver injury:emerging role of mitochondrial stress[J].J Gastroenterol Hepatol,2014,29(4):678-687.
[18] PESSAYRE D,MANSOURI A,BERSON A,et al.Mitochondrial involvement in drug-induced liverinjury[J].Handb Exp Pharmacol,2010(196):311-365.
[19] LEE KK,BOELSTERLI U A.By passing the compromised mitochondrial electron transport with methylene blue alleviates efavirenz/isoniazid-induced oxidant stress and mitochondria-mediated cell death in mouse hepatocytes[J].Redox Biol,2014,2:599-609.
[20] 张炜.抗结核药物致小鼠肝细胞线粒体损伤的研究[D].河北唐山:华北煤炭医学院,2010:22-26
[21] BHADAURIA S,SINGH G,SINHA N,et al.Isoniazid induces oxidative stress,mitochondrial dysfunction and apoptosis in HepG2 cells[J].Cell Mol Biol(Noisy-le-grand),2007,53(1):102-114.
[22] BHADAURIA S,MISHRA R,KANCHAN R,et al.Isoniazid-induced apoptosis in HepG2 cells:generation of oxidative stress and Bcl-2 down-regulation[J].Toxicol Mech Methods,2010,20(5):242-251.
[23] 郭瑶雪,邓晔,李春,等.异烟肼致线粒体损伤引起药物性肝损伤研究进展[J].中国临床药理学与治疗学,2015,20(3):356-360.
[24] WU Z R,BAI Z T,SUN Y,et al.Protective effects of the bioactive natural product N-trans-Caffeoyldopamine on hepatotoxicity induced by isoniazid and rifampicin[J].Bioorg Med Chem Lett,2015,25(22):5424-5426.
[25] CHEN X,XU J,ZHANG C,et al.The protective effects ofursodeoxycholic acid on isoniazid plus rifampicin induced liver injury in mice[J].Eur J Pharmacol,2011,659(1):53-60.
[26] CEDERBAUM A.Nrf2 and antioxidant Defense against CYP2E1toxicity[J].Expert Opin Drug Metab Toxicol,2009,5(10):1223-1244.
[27] HASSAN H M,GUO H L,YOUSEF B A,et al.Role of inflammatory and oxidative stress,cytochrome P450 2E1,and bile acid disturbance in rat liver injury induced by isoniazid and lipopolysaccharide cotreatment[J].Antimicrob Agents Chemother,2016,60(9):5285-5293.
[28] CHOWDHURY A,SANTRA A,BHATTACHARJEE K,et al.Mitochondrial oxidative stress and permeability transition inisoniazid and rifampicin induced liver injury in mice[J].J Hepatol,2006,45(1):117-126.
[29] YUE J,PENG R X,YANG J,et al.CYP2E1 mediatedisoniazid-induced hepatotoxicity in rats[J].Acta Pharmacol Sin,2004,25(5):699-704.
[30] SHENG Y J,WU G,HE H Y,et al.The association between CYP2E1 polymorphisms and hepatotoxicity due to anti-tuberculosis drugs:A meta-analysis[J].Infect Genet Evol,2014,24:34-40.
[31] CHEN YY,XUE P,HOU Y Y,et al.Isoniazid suppresses antioxidant response element activities and impairs adipogenesis in mouse and human preadipocytes[J].Toxicol Appl Pharmacol,2013,273(3):435-441.
[32] SAAD E I,EL-GOWILLY S M,SHERHAA M O,et al.Role of oxidative stress and nitric oxide in the protective effects of alpha-lipoic acid and aminoguanidine against isoniazid-rifampicin-induced hepatotoxicity in rats[J].Food Chem Toxicol,2010,48(7):1869-1875.
[33] PAL R,RANA S V,VAIPHEI K,et al.Isoniazid-rifampicin induced lipid changes in rats[J].Clin Chim Acta,2008,389(1-2):55-60.
[34] PALANISAMY N,MANIAN S.Protective effects of Asparagusracemosus on oxidative damage in isoniazid-induced hepatotoxic rats:An in vivo study[J].Toxicol Ind Health,2012,28(3):238-244.
[35] SHIH T Y,YOUNG T H,LEE H S,et al.Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity[J].AAPS J,2013,15(3):753-762.
[36] DONG Y Z,HUANG J C,LIN X,et al.Hepatoprotective effects of Yulangsan polysaccharide against isoniazid and rifampicin-induced liver injury in mice[J].J Ethnopharmacol,2014,152(1):201-206.
[37] LI F,LU J,CHENG J,et al.Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy[J].Nat Med,2013,19(4):418-420.
[38] SACHAR M,ANDERSON K E,MA X C.Protoporphyrin IX:the good,the bad,and the ugly[J].J Pharmacol Exp Ther,2016,356(2):267-275.
[39] FONTANA A O,PIFFARETTI D,MARCHI F,et al.Epithelial growth factor receptor expression influences 5-ALA induced glioblastoma fluorescence[J].J Neurooncol,2017,133(3):497-507.
[40] LYOUMI S,LEFEBVRE T,KARIM Z,et al.PXR-ALAS1:a key regulatory pathway in liver toxicity induced byisoniazid-rifampicin antituberculosis treatment[J].Clin Res Hepatol Gastroenterol,2013,37(5):439-441.
[41] SACHAR M,LI F,LIU K,et al.Chronic treatment with isoniazid causes protoporphyrin IX accumulation in mouse liver[J].Chem Res Toxicol,2016,29(8):1293-1297.
[42] JAMES L,ROBERTS D.Isoniazid hepatotoxicity:progress in understanding the immunologic component[J].Hepatology,2014,59(3):746-748.
[43] METUSHI I G,UETRECHT J.Isoniazid-induced liver injury and immune response in mice[J].J Immunotoxicol,2014,11(4):383-392.
[44] SALAZAR-PáRAMO M,RUBIN R L,GARCíA-DE LA TORRE I.Systemic lupuserythematosus induced by isoniazid[J].Ann Rheum Dis,1992,51(9):1085-1087.
[45] UETRECHT J.Immunoallergic drug-induced liver injury in humans[J].Semin Liver Dis,2009,29(4):383-392.
[46] METUSHI I G,SANDERS C,ACUTE LIVER STUDY GROUP,et al.Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure[J].Hepatology,2014,59(3):1084-1093.
[47] VIGNATI L,TURLIZZI E,MONACI S,et al.An in vitro approach to detect metabolite toxicity due to CYP3A4-dependent bioactivation of xenobiotics[J].Toxicology,2005,216(2-3):154-167.
[48] 张志华.异烟肼和利福平合用致肝细胞毒性及药物保护机制探讨[D].石家庄:河北医科大学,2009:62-64.
[49] WEN X,WANG J S,NEUVONEN P J,et al.Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2,2A6,2C19 and 3A4 isoforms in human liver microsomes[J].Eur J Clin Pharmacol,2002,57(11):799-804.
[50] LIU K,LI F,LU J,et al.Role of CYP3A inisoniazid metabolism in vivo[J].Drug Metab Pharmacokinet,2014,29(2):219-222.
[51] ORTEGA-ALONSO A,STEPHENS C,LUCENA M I,et al.Case characterization,clinical features and risk factors in drug-induced liver injury[J].Int J Mol Sci,2016,17(5):E714.
[52] 朱家莲,龚奕,彭文兴.异烟肼/利福平致肝损伤的生物标志物研究进展[J].中国医院药学杂志,2018,38(22):2380-2383.
[53] TASDUQ S A,PEERZADA K,KOUL S,et al.Biochemical manifestations of anti-tuberculosis drugs induced hepatotoxicity and the effect of silymarin[J].Hepatol Res,2005,31(3):132-135.
[54] WU Z R,BAI Z T,SUN Y,et al.Protective effects of the bioactive natural product N-trans-Caffeoyldopamine on hepatotoxicity induced by isoniazid and rifampicin[J].Bioorg Med Chem Lett,2015,25(22):5424-5426.
[2] Williams C.Global tuberculosis control:WHO report 2011[J].Austral New Zeal J Publ Health,2012,36(5):497-498.
[3] DEVARBHAVI H,DIERKHISING R,KREMERS W K.Antituberculosis therapy drug-induced liver injury and acute liver failure[J].Hepatology,2010,52(2):798-799.
[4] PARK W B,KIM W,LEE K L,et al.Antituberculosis drug-induced liver injury in chronic hepatitis and cirrhosis[J].J Infect,2010,61(4):323-329.
[5] YEW WW,LEUNG C C.Antituberculosis drugs and hepatotoxicity[J].Am J Respir Crit Care Med,2007,175(8):858.
[6] WANG P C,PRADHAN K,ZHONG X B,et al.Isoniazid metabolism and hepatotoxicity[J].Acta Pharm Sin B,2016,6(5):384-392.
[7] METUSHI I G,CAI P,ZHU X,et al.A fresh look at the mechanism of isoniazid-induced hepatotoxicity[J].Clin Pharmacol Ther,2011,89(6):911-914.
[8] MITCHELL J R,ZIMMERMAN H J,ISHAK K G,et al.Isoniazid liver injury:clinical spectrum,pathology,and probable pathogenesis[J].Ann Intern Med,1976,84(2):181-192.
[9] INGAWALE D K,MANDLIK S K,NAIK S R.Models ofhepatotoxicity and the underlying cellular,biochemical and immunological mechanism(s):A critical discussion[J].Environ Toxicol Pharmacol,2014,37(1):118-133.
[10] HASSAN H M,HONGLI G,YOUSEF B A,et al.Hepatotoxicity mechanisms of isoniazid:A mini-review[J].J Appl Toxicol,2015,35(12):1427-1432.
[11] BALó J.Role of hydrazine incarcinogenesis[J].Adv Cancer Res,1979,30:151-164.
[12] TIMPERIO A M,RINALDUCCI S,ZOLLA L.Hydrazide derivatives produce active oxygen species as hydrazine[J].Bioorg Chem,2005,33(6):459-469.
[13] PERWITASARI D A,ATTHOBARI J,WILFFERT B.Pharmacogenetics of isoniazid-induced hepatotoxicity[J].Drug Metab Rev,2015,47(2):222-228.
[14] GARROD S,BOLLARD M E,NICHOLLS A W,et al.Integrated metabonomic analysis of the multiorgan effects of hydrazine toxicity in the rat[J].Chem Res Toxicol,2005,18(2):115-122.
[15] BANDO K,KUNIMATSU T,JUN S K,et al.GC-MS-based metabolomics reveals mechanism of action for hydrazine induced hepatotoxicity in rats[J].J Appl Toxicol,2011,31(6):524-535.
[16] OLTHOF E,TOSTMANN A,PETERS W H,et al.Hydrazine-induced liver toxicity is enhanced by glutathione depletion but is not mediated by oxidative stress in HepG2 cells[J].Int J Antimicrob Agents,2009,34(4):385-386.
[17] BOELSTERLI U A,LEE KK.Mechanisms of isoniazid-induced idiosyncratic liver injury:emerging role of mitochondrial stress[J].J Gastroenterol Hepatol,2014,29(4):678-687.
[18] PESSAYRE D,MANSOURI A,BERSON A,et al.Mitochondrial involvement in drug-induced liverinjury[J].Handb Exp Pharmacol,2010(196):311-365.
[19] LEE KK,BOELSTERLI U A.By passing the compromised mitochondrial electron transport with methylene blue alleviates efavirenz/isoniazid-induced oxidant stress and mitochondria-mediated cell death in mouse hepatocytes[J].Redox Biol,2014,2:599-609.
[20] 张炜.抗结核药物致小鼠肝细胞线粒体损伤的研究[D].河北唐山:华北煤炭医学院,2010:22-26
[21] BHADAURIA S,SINGH G,SINHA N,et al.Isoniazid induces oxidative stress,mitochondrial dysfunction and apoptosis in HepG2 cells[J].Cell Mol Biol(Noisy-le-grand),2007,53(1):102-114.
[22] BHADAURIA S,MISHRA R,KANCHAN R,et al.Isoniazid-induced apoptosis in HepG2 cells:generation of oxidative stress and Bcl-2 down-regulation[J].Toxicol Mech Methods,2010,20(5):242-251.
[23] 郭瑶雪,邓晔,李春,等.异烟肼致线粒体损伤引起药物性肝损伤研究进展[J].中国临床药理学与治疗学,2015,20(3):356-360.
[24] WU Z R,BAI Z T,SUN Y,et al.Protective effects of the bioactive natural product N-trans-Caffeoyldopamine on hepatotoxicity induced by isoniazid and rifampicin[J].Bioorg Med Chem Lett,2015,25(22):5424-5426.
[25] CHEN X,XU J,ZHANG C,et al.The protective effects ofursodeoxycholic acid on isoniazid plus rifampicin induced liver injury in mice[J].Eur J Pharmacol,2011,659(1):53-60.
[26] CEDERBAUM A.Nrf2 and antioxidant Defense against CYP2E1toxicity[J].Expert Opin Drug Metab Toxicol,2009,5(10):1223-1244.
[27] HASSAN H M,GUO H L,YOUSEF B A,et al.Role of inflammatory and oxidative stress,cytochrome P450 2E1,and bile acid disturbance in rat liver injury induced by isoniazid and lipopolysaccharide cotreatment[J].Antimicrob Agents Chemother,2016,60(9):5285-5293.
[28] CHOWDHURY A,SANTRA A,BHATTACHARJEE K,et al.Mitochondrial oxidative stress and permeability transition inisoniazid and rifampicin induced liver injury in mice[J].J Hepatol,2006,45(1):117-126.
[29] YUE J,PENG R X,YANG J,et al.CYP2E1 mediatedisoniazid-induced hepatotoxicity in rats[J].Acta Pharmacol Sin,2004,25(5):699-704.
[30] SHENG Y J,WU G,HE H Y,et al.The association between CYP2E1 polymorphisms and hepatotoxicity due to anti-tuberculosis drugs:A meta-analysis[J].Infect Genet Evol,2014,24:34-40.
[31] CHEN YY,XUE P,HOU Y Y,et al.Isoniazid suppresses antioxidant response element activities and impairs adipogenesis in mouse and human preadipocytes[J].Toxicol Appl Pharmacol,2013,273(3):435-441.
[32] SAAD E I,EL-GOWILLY S M,SHERHAA M O,et al.Role of oxidative stress and nitric oxide in the protective effects of alpha-lipoic acid and aminoguanidine against isoniazid-rifampicin-induced hepatotoxicity in rats[J].Food Chem Toxicol,2010,48(7):1869-1875.
[33] PAL R,RANA S V,VAIPHEI K,et al.Isoniazid-rifampicin induced lipid changes in rats[J].Clin Chim Acta,2008,389(1-2):55-60.
[34] PALANISAMY N,MANIAN S.Protective effects of Asparagusracemosus on oxidative damage in isoniazid-induced hepatotoxic rats:An in vivo study[J].Toxicol Ind Health,2012,28(3):238-244.
[35] SHIH T Y,YOUNG T H,LEE H S,et al.Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity[J].AAPS J,2013,15(3):753-762.
[36] DONG Y Z,HUANG J C,LIN X,et al.Hepatoprotective effects of Yulangsan polysaccharide against isoniazid and rifampicin-induced liver injury in mice[J].J Ethnopharmacol,2014,152(1):201-206.
[37] LI F,LU J,CHENG J,et al.Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy[J].Nat Med,2013,19(4):418-420.
[38] SACHAR M,ANDERSON K E,MA X C.Protoporphyrin IX:the good,the bad,and the ugly[J].J Pharmacol Exp Ther,2016,356(2):267-275.
[39] FONTANA A O,PIFFARETTI D,MARCHI F,et al.Epithelial growth factor receptor expression influences 5-ALA induced glioblastoma fluorescence[J].J Neurooncol,2017,133(3):497-507.
[40] LYOUMI S,LEFEBVRE T,KARIM Z,et al.PXR-ALAS1:a key regulatory pathway in liver toxicity induced byisoniazid-rifampicin antituberculosis treatment[J].Clin Res Hepatol Gastroenterol,2013,37(5):439-441.
[41] SACHAR M,LI F,LIU K,et al.Chronic treatment with isoniazid causes protoporphyrin IX accumulation in mouse liver[J].Chem Res Toxicol,2016,29(8):1293-1297.
[42] JAMES L,ROBERTS D.Isoniazid hepatotoxicity:progress in understanding the immunologic component[J].Hepatology,2014,59(3):746-748.
[43] METUSHI I G,UETRECHT J.Isoniazid-induced liver injury and immune response in mice[J].J Immunotoxicol,2014,11(4):383-392.
[44] SALAZAR-PáRAMO M,RUBIN R L,GARCíA-DE LA TORRE I.Systemic lupuserythematosus induced by isoniazid[J].Ann Rheum Dis,1992,51(9):1085-1087.
[45] UETRECHT J.Immunoallergic drug-induced liver injury in humans[J].Semin Liver Dis,2009,29(4):383-392.
[46] METUSHI I G,SANDERS C,ACUTE LIVER STUDY GROUP,et al.Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure[J].Hepatology,2014,59(3):1084-1093.
[47] VIGNATI L,TURLIZZI E,MONACI S,et al.An in vitro approach to detect metabolite toxicity due to CYP3A4-dependent bioactivation of xenobiotics[J].Toxicology,2005,216(2-3):154-167.
[48] 张志华.异烟肼和利福平合用致肝细胞毒性及药物保护机制探讨[D].石家庄:河北医科大学,2009:62-64.
[49] WEN X,WANG J S,NEUVONEN P J,et al.Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2,2A6,2C19 and 3A4 isoforms in human liver microsomes[J].Eur J Clin Pharmacol,2002,57(11):799-804.
[50] LIU K,LI F,LU J,et al.Role of CYP3A inisoniazid metabolism in vivo[J].Drug Metab Pharmacokinet,2014,29(2):219-222.
[51] ORTEGA-ALONSO A,STEPHENS C,LUCENA M I,et al.Case characterization,clinical features and risk factors in drug-induced liver injury[J].Int J Mol Sci,2016,17(5):E714.
[52] 朱家莲,龚奕,彭文兴.异烟肼/利福平致肝损伤的生物标志物研究进展[J].中国医院药学杂志,2018,38(22):2380-2383.
[53] TASDUQ S A,PEERZADA K,KOUL S,et al.Biochemical manifestations of anti-tuberculosis drugs induced hepatotoxicity and the effect of silymarin[J].Hepatol Res,2005,31(3):132-135.
[54] WU Z R,BAI Z T,SUN Y,et al.Protective effects of the bioactive natural product N-trans-Caffeoyldopamine on hepatotoxicity induced by isoniazid and rifampicin[J].Bioorg Med Chem Lett,2015,25(22):5424-5426.