Correlation of Genetic Polymorphism In UGT1A1, SLCO1B1, NAT2, and CYP2E1 With Hepatotoxicity


  • Melisa Intan Barliana Department of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran
  • Gita W Setyowati Department of Biological Pharmacy, Biotechnology Pharmacy Laboratory, Faculty of Pharmacy, Universitas Padjadjaran
  • Nurul Annisa Department of Biological Pharmacy, Biotechnology Pharmacy Laboratory, Faculty of Pharmacy, Universitas Padjadjaran


Tuberculosis (TB) has identified as one of the most highly infectious diseases in the world. Tuberculosis can be identified as pulmonary or extrapulmonary. Therapy for TB is a combination of several drugs in one treatment. The effectiveness and toxicity of TB therapy may differ in each patient because of some risk factors, especially genetic variations. This review describes several genes that can affect the effectiveness and toxicity of antituberculosis drugs, namely UGT1A1, SLCO1B1, NAT2, and CYP2E1. This review was conducted utilizing the PubMed database, with keywords used as follows: polymorphism, antituberculosis, and tuberculosis. The presence of polymorphisms in these genes can result in hepatotoxicity and decreased drug bioavailability. Therefore, polymorphisms in these genes can determine the effectiveness of TB therapy.

Keywords: Antituberculosis drugs, genetic polymorphism, tuberculosis

Author Biography

Nurul Annisa, Department of Biological Pharmacy, Biotechnology Pharmacy Laboratory, Faculty of Pharmacy, Universitas Padjadjaran

1Department of Biological Pharmacy, Biotechnology Pharmacy Laboratory, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, Indonesia

2Unit of Clinical Pharmacy and Community, Faculty of Pharmacy, Universitas Mulawarman, Samarinda, Indonesia


1. Houben RMGJ, Dodd PJ. The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling. PLoS Med. 2016;13(10):1–13.
2. Uplekar M, Weil D, Lonnroth K, Jaramillo E, Lienhardt C, Dias HM, et al. WHO’s new end TB strategy. Lancet. 2015;385(9979):1799–801.
3. WHO. Moscow Declaration Ending Tb in the Sustainable Development Era. 2017;(November):1–8.
4. Sun Q, Zhang Q, Gu J, Sun W-W, Wang P, Bai C, et al. Prevalence, risk factors, management, and treatment outcomes of first-line antituberculous drug-induced liver injury: a prospective cohort study. Pharmacoepidemiol Drug Saf. 2016 Aug;25(8):908–17.
5. Gumbo T, Louie A, Deziel MR, Parsons LM, Salfinger M, Drusano GL. Selection of a Moxifloxacin Dose That Suppresses Drug Resistance in Mycobacterium tuberculosis, by Use of an In Vitro Pharmacodynamic Infection Model and Mathematical Modeling . J Infect Dis. 2004;190(9):1642–51.
6. Kruglyak L, Nickerson DA. Variation is the spice of life. Nat Genet [Internet]. 2001;27(3):234–6. Available from:
7. Balram C, Sabapathy K, Fei G, Khoo KS, Lee EJD. Genetic polymorphisms of UDP-glucuronosyltransferase in Asians:UGT1A1* 28 is a common allele in Indians. Pharmacogenet Genomics [Internet]. 2002;12(1). Available from:
8. Guillemette C, Millikan RC, Newman B, Housman DE. Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and association with breast cancer among African Americans. Cancer Res. 2000;60(4):950–6.
9. Zhang A, Xing Q, Qin S, Du J, Wang L, Yu L, et al. Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations. Pharmacogenomics J [Internet]. 2007;7(5):333–8. Available from:
10. Pacheco PR, Brilhante MJ, Ballart C, Sigalat F, Polena H, Cabral R, et al. UGT1A1, UGT1A6 and UGT1A7 Genetic Analysis. Mol Diagn Ther [Internet]. 2009;13(4):261–8. Available from:
11. Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics. 2006;16(12):873–9.
12. Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2007;82(6):726–33.
13. NCBI. NAT2 N-acetyltransferase 2 [Internet]. 2020. Available from:
14. NCBI. CYP2E1 cytochrome P450 family 2 subfamily E member 1 [Internet]. 2020. Available from:
15. 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.
16. Sun Q, Liu H, Zheng R, Wang P, Liu Z, Sha W, et al. Genetic Polymorphisms of SLCO1B1, CYP2E1 and UGT1A1 and Susceptibility to Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Chinese Population-Based Prospective Case–Control Study. Clin Drug Investig [Internet]. 2017;37(12):1125–36. Available from:
17. 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.
18. Chen R, Wang J, Tang S, Zhang Y, Lv X, Wu S, et al. Association of polymorphisms in drug transporter genes (SLCO1B1 and SLC10A1) and anti-tuberculosis drug-induced hepatotoxicity in a Chinese cohort. Tuberculosis. 2015;95(1):68–74.
19. Kim SH, Kim SH, Lee JH, Lee BH, Kim YS, Park JS, et al. Polymorphisms in drug transporter genes (ABCB1, SLCO1B1 and ABCC2) and hepatitis induced by antituberculosis drugs. Tuberculosis [Internet]. 2012;92(1):100–4. Available from:
20. Sloan DJ, McCallum AD, Schipani A, Egan D, Mwandumba HC, Ward SA, et al. Genetic determinants of the pharmacokinetic variability of rifampin in Malawian adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2017;61(7):1–9.
21. Dompreh A, Tang X, Zhou J, Yang H, Topletz A, Ahwireng A, et al. Effect of Genetic Variation of NAT2 on Isoniazid and SLCO1B1 and CES2 on Rifampin Pharmacokinetics in Ghanaian Children With Tuberculosis. 2018;62(3):1–11.
22. An HR, Wu XQ, Wang ZY, Zhang JX, Liang Y. NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug-induced hepatotoxicity in Chinese patients. Clin Exp Pharmacol Physiol. 2012;39(6):535–43.
23. 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 [Internet]. 2016;61(6):533–7. Available from:
24. Singla N, Gupta D, Birbian N, Singh J. Association of NAT2, GST and CYP2E1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity. Tuberculosis [Internet]. 2014;94(3):293–8. Available from:
25. Xiang Y, Ma L, Wu W, Liu W, Li Y, Zhu X, et al. The incidence of liver injury in uyghur patients treated for TB in Xinjiang Uyghur Autonomous Region, China, and its association with hepatic enzyme polymorphisms NAT2, CYP2E1, GSTM1 and GSTT1. PLoS One. 2014;9(1):1–8.
26. Ben Mahmoud L, Ghozzi H, Kamoun A, Hakim A, Hachicha H, Hammami S, 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 [Internet]. 2012;60(5):324–30. Available from:
27. Verhagen LM, Coenen MJ, López D, García JF, De Waard JH, Schijvenaars MM, et al. Full-gene sequencing analysis of NAT2 and its relationship with isoniazid pharmacokinetics in Venezuelan children with tuberculosis. Pharmacogenomics. 2014;15(3):285–96.
28. Kim SH, Kim SH, Yoon HJ, Shin DH, Park SS, Kim YS, et al. NAT2, CYP2C9, CYP2C19, and CYP2E1 genetic polymorphisms in anti-TB drug-induced maculopapular eruption. Eur J Clin Pharmacol. 2011;67(2):121–7.
29. Tang SW, Lv XZ, Zhang Y, Wu SS, Yang ZR, Xia YY, 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):588–93.
30. Tang S, Lv X, Zhang Y, Wu S, Yang Z, Xia Y, et al. Cytochrome P450 2E1 Gene Polymorphisms/Haplotypes and Anti-Tuberculosis Drug-Induced Hepatitis in a Chinese Cohort. PLoS One. 2013;8(2):1–7.
31. Sharma SK, Jha BK, Sharma A, Sreenivas V, Upadhyay V, Jaisinghani C, et al. Genetic polymorphisms of CYP2E1 and GSTM1 loci and susceptibility to anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung Dis. 2014;18(5):588–93.
32. Charbonneau DH, Healy AM. Genetics Home Reference. J Consum Health Internet. 2005;9(4):61–8.
33. Genetics Home Reference. UGT1A1 gene [Internet]. 2020. Available from:
34. Hennig S, Naiker S, Reddy T, Egan D, Kellerman T, Wiesner L, et al. Effect of SLCO1B1 polymorphisms on rifabutin pharmacokinetics in African HIV-infected patients with tuberculosis. Antimicrob Agents Chemother. 2015;60(1):617–20.
35. Weiner M, Peloquin C, Burman W, Luo CC, Engle M, Prihoda TJ, et al. Effects of tuberculosis, race, and human gene SLCO1B1 polymorphisms on rifampin concentrations. Antimicrob Agents Chemother. 2010;54(10):4192–200.
36. Bins S, Lenting A, El Bouazzaoui S, van Dorn L, Oomen-de Hoop E, Eskens FALM, et al. Polymorphisms in SLCO1B1 and UGT1A1 are associated with sorafenib-induced toxicity. Pharmacogenomics. 2016;17:1483–90.
37. Genetics Home Reference. SLCO1B1 gene [Internet]. 2020. Available from:
38. SNPedia. NAT2 [Internet]. 2020. Available from:
39. Genetics Home Reference. NAT2 gene [Internet]. 2020. Available from:
40. Teixeira RL de F, , Renata Gomes Morato1 PHC, Muniz2 LMK, Moreira2 A da SR, Afrânio Lineu Kritski2 FCQM, Suffys3 PN, et al. Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes.pdf. 2011;106(September):716–24.
41. Lee SW, Chung LSC, Huang HH, Chuang TY, Liou YH, Wu LSH. NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis. Int J Tuberc Lung Dis. 2010;14(5):622–6.
42. Wang T, Yu HT, Wang W, Pan YY, He LX, Wang ZY. 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):977–86.
43. Huang YS, Chern H Der, Su WJ, Wu JC, Chang SC, Chiang CH, et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology. 2003;37(4):924–30.
44. Ahlawat S, Sharma R, Maitra A, Roy M, Tantia MS. Designing, optimization and validation of tetra-primer ARMS PCR protocol for genotyping mutations in caprine Fec genes. Meta Gene [Internet]. 2014;2:439–49. Available from:
1 Views | Downloads
How to Cite
Barliana, M. I., Setyowati, G. W., & Annisa, N. (2020). Correlation of Genetic Polymorphism In UGT1A1, SLCO1B1, NAT2, and CYP2E1 With Hepatotoxicity. International Journal of Applied Pharmaceutics, 13(1). Retrieved from
Review Article(s)