Current Pharmacology Reports

, Volume 4, Issue 3, pp 171–181 | Cite as

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

  • Yifan Bao
  • Xiaochao Ma
  • Theodore P. Rasmussen
  • Xiao-bo Zhong
Drug-Induced Liver Injury (X Ma, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Drug-induced Liver Injury


Purpose of this Review

In order to combat the development of drug resistance, the clinical treatment of tuberculosis requires the combined use of several anti-tuberculosis (anti-TB) drugs, including isoniazid and rifampicin. Combinational treatment approaches are suggested by the World Health Organization (WHO) and are widely accepted throughout the world. Unfortunately, a major side effect of the treatment is the development of anti-tuberculosis drug-induced liver injury (AT-DILI). Many factors contribute to isoniazid- and rifampicin-mediated AT-DILI and genetic variations are among the most common factors. The purpose of this review is to provide information on genetic variations associated with isoniazid- and rifampicin-mediated AT-DILI.

Recent Findings

The genetic variations associated with AT-DILI have been identified in the genomic regions within or near genes encoding proteins in the following pathways: drug metabolizing enzymes (NAT2, CYP2E1, and GSTs), accumulation of bile acids, lipids, and heme metabolites (CYP7A1, BSEP, UGTs, and PXR), immune adaptation (HLAs and TNF-α), and oxidant challenge (TXNRD1, SOD1, BACH1, and MAFK).


The information summarized in this review considers the genetic bases of risk factors contributing to AT-DILI and provides information that may help for future studies. Some of the implicated genetic variations can be used in the design of genetic tests and serve as biomarkers for the prediction of isoniazid- and rifampicin-mediated AT-DILI risk in personalized medicine.


Anti-tuberculosis drugs Drug-induced liver injury Genetic variations Isoniazid Rifampicin 



This work was supported in part by grants from the National Institute of General Medical Sciences [Grant R01GM-118367] (to X.B.Z. and X.M.), the National Institute for Environmental Health Science [Grant R01ES-019487] (to X.B.Z.), the National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01DK-090305] (to X.M.), and the National Institute of Allergy And Infectious Diseases (Grant R01AI-131983) (to X.M.).

Compliance with Ethical Standards

Conflict of Interest

None of the authors has a conflict of interest to declare in relation to this work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human and animal subjects performed by any of the authors.


  1. 1.
    Caminero JA, Scardigli A. Classification of antituberculosis drugs: a new proposal based on the most recent evidence. Eur Respir J. 2015;46(4):887–93.CrossRefPubMedGoogle Scholar
  2. 2.
    Tiberi S, Scardigli A, Centis R, D’Ambrosio L, Muñoz-Torrico M, Salazar-Lezama MÁ, et al. Classifying new anti-tuberculosis drugs: rationale and future perspectives. Int J Infect Dis. 2017;56:181–4.CrossRefPubMedGoogle Scholar
  3. 3.
    Isa SE, Ebonyi AO, Shehu NY, Idoko P, Anejo-Okopi JA, Simji G, et al. Antituberculosis drugs and hepatotoxicity among hospitalized patients in Jos, Nigeria. Int J Mycobacteriol. 2016;5(1):21–6.CrossRefPubMedGoogle Scholar
  4. 4.
    WHO Guidelines Approved by the Guidelines Review Committee. In: Guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Geneva: World Health Organization World Health Organization; 2011.Google Scholar
  5. 5.
    Chouchane S, Lippai I, Magliozzo RS. Catalase-peroxidase (mycobacterium tuberculosis KatG) catalysis and isoniazid activation. Biochemistry. 2000;39(32):9975–83.CrossRefPubMedGoogle Scholar
  6. 6.
    Somoskovi A, Parsons LM, Salfinger M. The molecular basis of resistance to isoniazid, rifampin, and pyrazinamide in mycobacterium tuberculosis. Respir Res. 2001;2(3):164–8.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lees AW, Allan GW, Smith J, Tyrrell WF, Fallon RJ. Toxicity form rifampicin plus isoniazid and rifampicin plus ethambutol therapy. Tubercle. 1971;52(3):182–90.CrossRefPubMedGoogle Scholar
  8. 8.
    Smith J, Tyrrell WF, Gow A, Allan GW, Lees AW. Hepatotoxicity in rifampin-isoniazid treated patients related to their rate of isoniazid inactivation. Chest. 1972;61(6):587–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Gangadharam PR. Isoniazid, rifampin, and hepatotoxicity. Am Rev Respir Dis. 1986;133(6):963–5.PubMedGoogle Scholar
  10. 10.
    Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990;11(2):272–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Ichai P, Saliba F, Antoun F, Azoulay D, Sebagh M, Antonini TM, et al. Acute liver failure due to antitubercular therapy: strategy for antitubercular treatment before and after liver transplantation. Liver Transpl. 2010;16(10):1136–46.CrossRefPubMedGoogle Scholar
  12. 12.
    Devarbhavi H, Karanth D, KS P, CK A, Patil M. Drug-induced liver injury with hypersensitivity features has a better outcome: a single-center experience of 39 children and adolescents. Hepatology. 2011;54(4):1344–50.CrossRefPubMedGoogle Scholar
  13. 13.
    Abbasi MA, et al. Common risk factors for the development of anti tuberculosis treatment induced hepatotoxicity. J Ayub Med Coll Abbottabad. 2014;26(3):384–8.PubMedGoogle Scholar
  14. 14.
    Shu CC, Lee CH, Lee MC, Wang JY, Yu CJ, Lee LN. 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):934–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Chien JY, Huang RM, Wang JY, Ruan SY, Chien YJ, Yu CJ, et al. Hepatitis C virus infection increases hepatitis risk during anti-tuberculosis treatment. Int J Tuberc Lung Dis. 2010;14(5):616–21.PubMedGoogle Scholar
  16. 16.
    Lomtadze N, Kupreishvili L, Salakaia A, Vashakidze S, Sharvadze L, Kempker RR, et al. Hepatitis C virus co-infection increases the risk of anti-tuberculosis drug-induced hepatotoxicity among patients with pulmonary tuberculosis. PLoS One. 2013;8(12):e83892.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Tasduq SA, Kaisar P, Gupta DK, Kapahi BK, Jyotsna S, Maheshwari HS, et al. Protective effect of a 50% hydroalcoholic fruit extract of Emblica officinalis against anti-tuberculosis drugs induced liver toxicity. Phytother Res. 2005;19(3):193–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Tasduq SA, Singh K, Satti NK, Gupta DK, Suri KA, Johri RK. Terminalia Chebula (fruit) prevents liver toxicity caused by sub-chronic administration of rifampicin, isoniazid and pyrazinamide in combination. Hum Exp Toxicol. 2006;25(3):111–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Amir M, Khan MA, Ahmad S, Akhtar M, Mujeeb M, Ahmad A, et al. Ameliorating effects of Tamarindus Indica fruit extract on anti-tubercular drugs induced liver toxicity in rats. Nat Prod Res. 2016;30(6):715–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Martin SJ, Baskaran UL, Vedi M, Sabina EP. Attenuation of anti-tuberculosis therapy induced hepatotoxicity by Spirulina Fusiformis, a candidate food supplement. Toxicol Mech Methods. 2014;24(8):584–92.CrossRefPubMedGoogle Scholar
  21. 21.
    Wang P, Pradhan K, Zhong XB, Ma X. Isoniazid metabolism and hepatotoxicity. Acta Pharm Sin B. 2016;6(5):384–92.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Metushi I, Uetrecht J, Phillips E. Mechanism of isoniazid-induced hepatotoxicity: then and now. Br J Clin Pharmacol. 2016;81(6):1030–6.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hassan HM, Guo HL, Yousef BA, Luyong Z, Zhenzhou J. Hepatotoxicity mechanisms of isoniazid: a mini-review. J Appl Toxicol. 2015;35(12):1427–32.CrossRefPubMedGoogle Scholar
  24. 24.
    Russmann S, Jetter A, Kullak-Ublick GA. Pharmacogenetics of drug-induced liver injury. Hepatology. 2010;52(2):748–61.CrossRefPubMedGoogle Scholar
  25. 25.
    Li F, Miao Y, Zhang L, Neuenswander SA, Douglas JT, Ma X. Metabolomic analysis reveals novel isoniazid metabolites and hydrazones in human urine. Drug Metab Pharmacokinet. 2011;26(6):569–76.CrossRefPubMedGoogle Scholar
  26. 26.
    Metushi IG, Nakagawa T, Uetrecht J. Direct oxidation and covalent binding of isoniazid to rodent liver and human hepatic microsomes: humans are more like mice than rats. Chem Res Toxicol. 2012;25(11):2567–76.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Li F, Lu J, Cheng J, Wang L, Matsubara T, Csanaky IL, et al. Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy. Nat Med. 2013;19(4):418–20.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Guo YX, Xu XF, Zhang QZ, Li C, Deng Y, Jiang P, et al. The inhibition of hepatic bile acids transporters Ntcp and Bsep is involved in the pathogenesis of isoniazid/rifampicin-induced hepatotoxicity. Toxicol Mech Methods. 2015;25(5):382–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Sharma R, Kaur R, Mukesh M, Sharma VL. Assessment of hepatotoxicity of first-line anti-tuberculosis drugs on Wistar rats. Naunyn Schmiedebergs Arch Pharmacol. 2018;391(1):83–93.CrossRefPubMedGoogle Scholar
  30. 30.
    Huang JH, Zhang C, Zhang DG, Li L, Chen X, Xu DX. Rifampicin-induced hepatic lipid accumulation: association with up-regulation of peroxisome proliferator-activated receptor gamma in mouse liver. PLoS One. 2016;11(11):e0165787.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kim JH, Nam WS, Kim SJ, Kwon OK, Seung EJ, Jo JJ, et al. Mechanism investigation of rifampicin-induced liver injury using comparative toxicoproteomics in mice. Int J Mol Sci. 2017;18(7):E1417.CrossRefPubMedGoogle Scholar
  32. 32.
    Sachar M, Anderson KE, Ma X. Protoporphyrin IX: the good, the bad, and the ugly. J Pharmacol Exp Ther. 2016;356(2):267–75.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lee RG, Avner DL, Berenson MM. Structure-function relationships of protoporphyrin-induced liver injury. Arch Pathol Lab Med. 1984;108(9):744–6.PubMedGoogle Scholar
  34. 34.
    Puy H, Gouya L, Deybach JC. Porphyrias. Lancet. 2010;375(9718):924–37.CrossRefPubMedGoogle Scholar
  35. 35.
    He L, Guo Y, Deng Y, Li C, Zuo C, Peng W. Involvement of protoporphyrin IX accumulation in the pathogenesis of isoniazid/rifampicin-induced liver injury: the prevention of curcumin. Xenobiotica. 2017;47(2):154–63.CrossRefPubMedGoogle Scholar
  36. 36.
    Sachar M, Li F, Liu K, Wang P, Lu J, Ma X. Chronic treatment with isoniazid causes Protoporphyrin IX accumulation in mouse liver. Chem Res Toxicol. 2016;29(8):1293–7.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Metushi IG, Sanders C, The Acute Liver Study Group, Lee WM, Uetrecht J. Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure. Hepatology. 2014;59(3):1084–93.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Usui T, Meng X, Saide K, Farrell J, Thomson P, Whitaker P, et al. From the cover: characterization of isoniazid-specific T-cell clones in patients with anti-tuberculosis drug-related liver and skin injury. Toxicol Sci. 2017;155(2):420–31.CrossRefPubMedGoogle Scholar
  39. 39.
    Metushi IG, Cai P, Vega L, Grant DM, Uetrecht J. Paradoxical attenuation of autoimmune hepatitis by oral isoniazid in wild-type and N-acetyltransferase-deficient mice. Drug Metab Dispos. 2014;42(6):963–73.CrossRefPubMedGoogle Scholar
  40. 40.
    Nicoletti NF, Rodrigues-Junior V, Santos AA Jr, Leite CE, Dias ACO, Batista EL Jr, et al. Protective effects of resveratrol on hepatotoxicity induced by isoniazid and rifampicin via SIRT1 modulation. J Nat Prod. 2014;77(10):2190–5.CrossRefPubMedGoogle Scholar
  41. 41.
    Chowdhury A, Santra A, Bhattacharjee K, Ghatak S, Saha DR, Dhali GK. Mitochondrial oxidative stress and permeability transition in isoniazid and rifampicin induced liver injury in mice. J Hepatol. 2006;45(1):117–26.CrossRefPubMedGoogle Scholar
  42. 42.
    Ji GY, Wang Y, Wu SQ, Liu QQ, Wu JC, Zhang MM, et al. Association between TXNRD1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in a prospective study. Genet Mol Res. 2016;15(3).
  43. 43.
    Tobe R, Yoo MH, Fradejas N, Carlson BA, Calvo S, Gladyshev VN, et al. Thioredoxin reductase 1 deficiency enhances selenite toxicity in cancer cells via a thioredoxin-independent mechanism. Biochem J. 2012;445(3):423–30.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Rosen DR. Mutations in cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;364(6435):362.CrossRefPubMedGoogle Scholar
  45. 45.
    Elchuri S, Oberley TD, Qi W, Eisenstein RS, Jackson Roberts L, van Remmen H, et al. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene. 2005;24(3):367–80.CrossRefPubMedGoogle Scholar
  46. 46.
    Okita Y, Kamoshida A, Suzuki H, Itoh K, Motohashi H, Igarashi K, et al. Transforming growth factor-beta induces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene. J Biol Chem. 2013;288(28):20658–67.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    McDonagh EM, et al. PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2. Pharmacogenet Genomics. 2014;24(8):409–25.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Cai Y, Yi JY, Zhou CH, Shen XZ. Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis. PLoS One. 2012;7(10):e47769.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Wattanapokayakit S, Mushiroda T, Yanai H, Wichukchinda N, Chuchottawon C, Nedsuwan S, et al. NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients. Int J Tuberc Lung Dis. 2016;20(10):1364–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Yuliwulandari R, Susilowati RW, Wicaksono BD, Viyati K, Prayuni K, Razari I, et al. NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis. J Hum Genet. 2016;61(6):533–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Chan SL, Chua APG. Association and clinical utility of NAT2 in the prediction of isoniazid-induced liver injury in Singaporean patients. PLoS One. 2017;12(10):e0186200.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Guaoua S, Ratbi I, el Bouazzi O, Hammi S, Tebaa A, Bourkadi JE, et al. NAT2 genotypes in Moroccan patients with hepatotoxicity due to Antituberculosis drugs. Genet Test Mol Biomarkers. 2016;20(11):680–4.CrossRefPubMedGoogle Scholar
  53. 53.
    Mushiroda T, Yanai H, Yoshiyama T, Sasaki Y, Okumura M, Ogata H, et al. Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients. Hum Genome Var. 2016;3:16014.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Li F, Wang P, Liu K, Tarrago MG, Lu J, Chini EN, et al. A high dose of isoniazid disturbs Endobiotic homeostasis in mouse liver. Drug Metab Dispos. 2016;44(11):1742–51.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Wang P, Shehu AI, Lu J, Joshi RH, Venkataramanan R, Sugamori KS, et al. Deficiency of N-acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver. Biochem Pharmacol. 2017;145:218–25.CrossRefPubMedGoogle Scholar
  56. 56.
    Sim SC, Ingelman-Sundberg M. The human cytochrome P450 (CYP) allele nomenclature website: a peer-reviewed database of CYP variants and their associated effects. Hum Genomics. 2010;4(4):278–81.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Sheng YJ, Wu G, He HY, Chen W, Zou YS, Li Q, et al. The association between CYP2E1 polymorphisms and hepatotoxicity due to anti-tuberculosis drugs: a meta-analysis. Infect Genet Evol. 2014;24:34–40.CrossRefPubMedGoogle Scholar
  58. 58.
    Wang FJ, Wang Y, Niu T, Lu WX, Sandford AJ, He JQ. Update meta-analysis of the CYP2E1 RsaI/PstI and DraI polymorphisms and risk of antituberculosis drug-induced hepatotoxicity: evidence from 26 studies. J Clin Pharm Ther. 2016;41(3):334–40.CrossRefPubMedGoogle Scholar
  59. 59.
    Shih TY, Young TH, Lee HS, Hsieh CB, Hu OYP. Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity. AAPS J. 2013;15(3):753–62.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Shih TY, Ho SC, Hsiong CH, Huang TY, Hu O. Selected pharmaceutical excipient prevent isoniazid and rifampicin induced hepatotoxicity. Curr Drug Metab. 2013;14(6):720–8.CrossRefPubMedGoogle Scholar
  61. 61.
    Cheng J, Krausz KW, Li F, Ma X, Gonzalez FJ. CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid. Toxicol Appl Pharmacol. 2013;266(2):245–53.CrossRefPubMedGoogle Scholar
  62. 62.
    Tang SW, Lv XZ, Chen R, Wu SS, Yang ZR, Chen DF, et al. Lack of association between genetic polymorphisms of CYP3A4, CYP2C9 and CYP2C19 and antituberculosis drug-induced liver injury in a community-based Chinese population. Clin Exp Pharmacol Physiol. 2013;40(5):326–32.CrossRefPubMedGoogle Scholar
  63. 63.
    Liu K, Li F, Lu J, Gao Z, Klaassen CD, Ma X. Role of CYP3A in isoniazid metabolism in vivo. Drug Metab Pharmacokinet. 2014;29(2):219–22.CrossRefPubMedGoogle Scholar
  64. 64.
    Singla N, Gupta D, Birbian N, Singh J. Association of NAT2, GST and CYP2E1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity. Tuberculosis (Edinb). 2014;94(3):293–8.CrossRefGoogle Scholar
  65. 65.
    Li C, Long J, Hu X, Zhou Y. GSTM1 and GSTT1 genetic polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity: an updated meta-analysis. Eur J Clin Microbiol Infect Dis. 2013;32(7):859–68.CrossRefPubMedGoogle Scholar
  66. 66.
    Cai L, Cai MH, Wang MY, Xu YF, Chen WZ, Qin SY, et al. Meta-analysis-based preliminary exploration of the connection between ATDILI and schizophrenia by GSTM1/T1 gene polymorphisms. PLoS One. 2015;10(6):e0128643.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Wu S, Wang YJ, Tang X, Wang Y, Wu J, Ji G, et al. Genetic polymorphisms of glutathione S-transferase P1 (GSTP1) and the incidence of anti-tuberculosis drug-induced hepatotoxicity. PLoS One. 2016;11(6):e0157478.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Traynor C, Conlon P Jr, Phelan PJ, O’Kelly P, Elens L, McCormack M, et al. Association of CYP3A variants with kidney transplant outcomes. Ren Fail. 2015;37(4):562–6.CrossRefPubMedGoogle Scholar
  69. 69.
    Norlin M, Wikvall K. Enzymes in the conversion of cholesterol into bile acids. Curr Mol Med. 2007;7(2):199–218.CrossRefPubMedGoogle Scholar
  70. 70.
    Nakamoto K, Wang S, Jenison RD, Guo GL, Klaassen CD, Wan YJ, et al. Linkage disequilibrium blocks, haplotype structure, and htSNPs of human CYP7A1 gene. BMC Genet. 2006;7:29.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Li Q, Hong J, Wu J, Huang ZX, Li QJ, Yin RX, et al. The role of common variants of ABCB1 and CYP7A1 genes in serum lipid levels and lipid-lowering efficacy of statin treatment: a meta-analysis. J Clin Lipidol. 2014;8(6):618–29.CrossRefPubMedGoogle Scholar
  72. 72.
    Cai Q, Wang ZQ, Cai Q, Li C, Chen EZ, Jiang ZY. Relationship between CYP7A1 -204A>C polymorphism with gallbladder stone disease and serum lipid levels: a meta-analysis. Lipids Health Dis. 2014;13:126.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Joshi AD, Andersson C, Buch S, Stender S, Noordam R, Weng LC, et al. Four susceptibility loci for gallstone disease identified in a meta-analysis of genome-wide association studies. Gastroenterology. 2016;151(2):351–63. e28CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Iwanicki T, et al. CYP7A1 gene polymorphism located in the 5′ upstream region modifies the risk of coronary artery disease. Dis Markers. 2015;2015:185969.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Inamine T, Higa S, Noguchi F, Kondo S, Omagari K, Yatsuhashi H, et al. Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients. J Gastroenterol. 2013;48(10):1160–70.CrossRefPubMedGoogle Scholar
  76. 76.
    Qrafli M, et al. The CYP7A1 gene rs3808607 variant is associated with susceptibility of tuberculosis in Moroccan population. Pan Afr Med J. 2014;18:1.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Chen R, Wang J, Tang SW, Zhang Y, Lv XZ, Wu SS, et al. CYP7A1, BAAT and UGT1A1 polymorphisms and susceptibility to anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung Dis. 2016;20(6):812–8.CrossRefPubMedGoogle Scholar
  78. 78.
    Stieger B. Role of the bile salt export pump, BSEP, in acquired forms of cholestasis. Drug Metab Rev. 2010;42(3):437–45.CrossRefPubMedGoogle Scholar
  79. 79.
    Chen R, Wang J, Tang S, Zhang Y, Lv X, Wu S, et al. Role of polymorphic bile salt export pump (BSEP, ABCB11) transporters in anti-tuberculosis drug-induced liver injury in a Chinese cohort. Sci Rep. 2016;6:27750.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Chang JC, Liu EH, Lee CN, Lin YC, Yu MC, Bai KJ, et al. UGT1A1 polymorphisms associated with risk of induced liver disorders by anti-tuberculosis medications. Int J Tuberc Lung Dis. 2012;16(3):376–8.CrossRefPubMedGoogle Scholar
  81. 81.
    Chen G, Wu SQ, Feng M, Wang Y, Wu JC, Ji GY, et al. Association of UGT2B7 polymorphisms with risk of induced liver injury by anti-tuberculosis drugs in Chinese Han. Int J Immunopathol Pharmacol. 2017;30(4):434–8.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Wang JY, Tsai CH, Lee YL, Lee LN, Hsu CL, Chang HC, et al. Gender-dimorphic impact of PXR genotype and haplotype on hepatotoxicity during Antituberculosis treatment. Medicine (Baltimore). 2015;94(24):e982.CrossRefGoogle Scholar
  83. 83.
    Zazuli Z, Barliana MI, Mulyani UA, Perwitasari DA, Ng H, Abdulah R. Polymorphism of PXR gene associated with the increased risk of drug-induced liver injury in Indonesian pulmonary tuberculosis patients. J Clin Pharm Ther. 2015;40(6):680–4.CrossRefPubMedGoogle Scholar
  84. 84.
    Wang YM, Chai SC, Brewer CT, Chen T. Pregnane X receptor and drug-induced liver injury. Expert Opin Drug Metab Toxicol. 2014;10(11):1521–32.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Lamba J, Lamba V, Strom S, Venkataramanan R, Schuetz E. Novel single nucleotide polymorphisms in the promoter and intron 1 of human pregnane X receptor/NR1I2 and their association with CYP3A4 expression. Drug Metab Dispos. 2008;36(1):169–81.CrossRefPubMedGoogle Scholar
  86. 86.
    Ye YM, Hur GY, Kim SH, Ban GY, Jee YK, Naisbitt DJ, et al. Drug-specific CD4+ T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms syndrome. Br J Dermatol. 2017;176(2):378–86.CrossRefPubMedGoogle Scholar
  87. 87.
    Chen R, Zhang Y, Tang S, Lv X, Wu S, Sun F, et al. The association between HLA-DQB1 polymorphism and antituberculosis drug-induced liver injury: a case-control study. J Clin Pharm Ther. 2015;40(1):110–5.CrossRefPubMedGoogle Scholar
  88. 88.
    Kuranov AB, Kozhamkulov UA, Vavilov MN, Belova ES, Bismilda VL, Alenova AH, et al. HLA-class II alleles in patients with drug-resistant pulmonary tuberculosis in Kazakhstan. Tissue Antigens. 2014;83(2):106–12.CrossRefPubMedGoogle Scholar
  89. 89.
    Kim SH, Kim SH, Yoon HJ, Shin DH, Park SS, Kim YS, et al. TNF-alpha genetic polymorphism -308G/a and antituberculosis drug-induced hepatitis. Liver Int. 2012;32(5):809–14.CrossRefPubMedGoogle Scholar
  90. 90.
    Elahi MM, Asotra K, Matata BM, Mastana SS. Tumor necrosis factor alpha −308 gene locus promoter polymorphism: an analysis of association with health and disease. Biochim Biophys Acta. 2009;1792(3):163–72.CrossRefPubMedGoogle Scholar
  91. 91.
    Kwon JW, Shin ES, Lee JE, Kim SH, Kim SH, Jee YK, et al. Genetic variations in TXNRD1 as potential predictors of drug-induced liver injury. Allergy Asthma Immunol Res. 2012;4(3):132–6.CrossRefPubMedGoogle Scholar
  92. 92.
    Kim SH, Kim SH, Lee JH, Lee BH, Yoon HJ, Shin DH, et al. Superoxide dismutase gene (SOD1, SOD2, and SOD3) polymorphisms and Antituberculosis drug-induced hepatitis. Allergy Asthma Immunol Res. 2015;7(1):88–91.CrossRefPubMedGoogle Scholar
  93. 93.
    Nanashima K, Mawatari T, Tahara N, Higuchi N, Nakaura A, Inamine T, et al. Genetic variants in antioxidant pathway: risk factors for hepatotoxicity in tuberculosis patients. Tuberculosis. 2012;92(3):253–9.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, School of PharmacyUniversity of ConnecticutStorrsUSA
  2. 2.Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of PharmacyUniversity of PittsburghPittsburghUSA

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