Int J App Pharm, Vol 13, Issue 1, 2021, 53-58Review Article

CORRELATION OF GENETIC POLYMORPHISM IN UGT1A1, SLCO1B1, NAT2, AND CYP2E1 WITH HEPATOTOXICITY

GITA WIDI SETYOWATI1, NURUL ANNISA1,2, MELISA I. BARLIANA1,3

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, 3Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Bandung, Indonesia
Email: melisa.barliana@unpad.ac.id

Received: 25 Aug 2020, Revised and Accepted: 14 Oct 2020

ABSTRACT

Tuberculosis (TB) has been 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

© 2021 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijap.2021v13i1.39540. Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION

Between a quarter and a third of the world’s population have been identified to be latently infected with Mycobacterium tuberculosis [1]. Approximately 1.2 million (around 1.1–1.3 million) tuberculosis (TB) deaths were recorded among Human Immunodeficiency Virus (HIV)-negative people in 2018 (a 27% reduction from 1.7 million in 2000) and an additional 251,000 deaths (around 223,000–281,000) [2]. Most TB cases in 2018 are in the Southeast Asian region (44%), Africa (24%), and the Western Pacific (18%), while smaller percentages are determined to be in the Eastern Mediterranean (8%), America (3%), and Europe (3%). Eight countries accounted for two-thirds of the global total, namely India (27%), China (9%), Indonesia (8%), Philippines (6%), Pakistan (6%), Nigeria (4%), Bangladesh (4%), and South Africa (3%) [3]. The effectiveness of antituberculosis drugs can differ in each patient. At some point, these drugs can cause adverse reactions [4]. Some adverse reactions to antituberculosis drugs affect the outcomes of treatment and probably cause treatment failure. The predominant of adverse reactions were gastrointestinal disorders, drug-induced hepatotoxicity [5], musculoskeletal disorders, central dan peripheral nervous system disorders, and less vision disorder [6]. Some risk factors for decreased liver function are malnutrition, alcohol consumptions [7], and genetics factor [8]. Genetics factors that cause drug effects such as the presence of gene polymorphisms in patients. Genetic factors in patients can cause poor therapeutic outcomes as well as an increased risk of drug resistance [9].

A single nucleotide mutation, referred to as single nucleotide polymorphisms (SNPs), can cause such variations in drug response. SNPs occur when a nucleotide is substituted erroneously within an allele, which may be unique or common to many individuals in the human population. SNPs occur in a variety of DNA [10]. Based on current literature, genes that can affect the responses of drugs in TB patients are UDP-glucuronosyltransferase 1A1 (UGT1A1), solute carrier organic anion transporter family member 1B1 (SLCO1B1), N-acetyltransferase 2 (NAT2), and cytochrome P450 2E1 (CYP2E1). UGT1A1 has been identified as a phase II drug metabolism enzyme that is important in conjugation and elimination of xenobiotics, carcinogens, and drugs [11–13]. The presence of polymorphisms in UGT1A1 causes a decrease in enzyme activity, resulting in pharmacokinetic differences from drugs [14]. SLCO1B1 is a gene that encodes transporters with a role in drug metabolism, specifically organic anion transporting polypeptide (OATP). Genetic variations of this gene can change the activity of transporters, leading to changes in pharmacokinetics and drug efficacy [15, 16]. NAT2 is a gene that codes for enzymes that activate and deactivate drugs. The polymorphism in this gene has been identified to be related to the N-acetylation polymorphism, which determines fast, medium, and slow acetylator phenotypes. Polymorphisms in this gene are also associated with high drug toxicity [17]. CYP2E1 is a gene that codes for the cytochrome P450 enzyme, which catalyzes reactions in drug metabolism [18].

Methods

This review included studies published in PubMed obtained using the keywords "polymorphism," "antituberculosis," and "tuberculosis." Additionally, annual reports released by the World Health Organization were included. However, reviews, non-English studies, and non-human studies were excluded. Of the 179 studies, we included 17 studies that focused on the relationship between gene polymorphisms and antituberculosis drugs, namely UGT1A1, SLCO1B1, NAT2, and CYP2E1 (fig. 1).

Fig. 1: Flowchart of the literature search process

DISCUSSION

The varying efficacy and toxicity of drugs are still identified to be a problem, causing harm to patients who are struggling to recover from their illness. Identifying the genetic differences in each patient can help the clinician adjust dosing and improve the results of therapy. This review further describes the influence of several genes, such as UGT1A1, SLCO1B1, NAT2, and CYP2E1, which might be associated with antituberculosis drug response (table 1). However, the results obtained from each population may be different.

Table 1: Association gene polymorphisms with the responses of antituberculosis drugs

Gene Polymorphism Study population Discussion Ref
Number Ethnic
UGT1A1

UGT1A1*27 (686C>A)

UGT1A1*28 [(TA)6→(TA)7]

 98 Taiwanese There is an association between gene polymorphism and elevated antituberculosis drug-induced hepatotoxicity risk [19]
rs4148323 A/A 927 Chinese Gene polymorphism with A/A genotype significantly could reduce antituberculosis drug-induced hepatotoxicity risk [20]

rs4148323

rs8330

 445 Chinese No significant association between gene polymorphism and antituberculosis drug-induced hepatotoxicity risk [21]
SLCO1B1 SLCO1B1*15 445 Chinese Patient with one haplotype of SLCO1B1*15 could have a higher risk of antituberculosis drug-induced hepatotoxicity than others with SLCO1B1*1a or SLCO1B1*1b [22]

rs4149034 G/A

rs1564370 G/C

rs2900478 T/A

rs2417957 T/T

rs4149063 T/T

 927 Chinese Patients with rs4149034 G/A, rs1564370 G/C, and rs2900478 T/A polymorphism could have a lower risk of antituberculosis drug-induced hepatotoxicity. While a patient with rs2417957 T/T and rs4149063 T/T polymorphism could have a higher risk of antituberculosis drug-induced hepatotoxicity [20]

rs4149013, rs4149014

rs2306283, rs4149056

 226 Korean No association between gene polymorphism with the development of antituberculosis drug-induced hepatotoxicity risk [23]
rs4149032 rs11045819 174 Black African Did not explain variability in AUC0–∞ of rifampin [24]
rs2306283 113 Ghanaian Patients with homozygous *1b variants (AA genotype) significantly decreased Cmax and AUC0–8h of rifampicin compared to wildtype (GG genotype) [25]
NAT2

rs1041983 (282TT)

rs1799930 (590AA)

rs1799931 (857GA)

 208 Chinese Gene polymorphism could higher development of antituberculosis drug-induced hepatotoxicity [26]
rs1799930 (NAT2*6A) 241 Indonesian Gene polymorphism could higher development of antituberculosis drug-induced hepatotoxicity [27]

rs1799929

rs1799930

rs1799931

 408 Indian Gene polymorphism could higher development of antituberculosis drug-induced hepatotoxicity [28]
rs1799929 2244 Uyghur There is an association between genetic polymorphism and antituberculosis drug-induced hepatotoxicity higher in a patient with CT genotype than CC genotype [29]

rs1799929

rs1799930

 66 Tunisian Polymorphism of rs1799929 (CC genotype) and rs1799930 (GG genotype) associated with decreasing antituberculosis drug-induced hepatotoxicity, while rs1799929 (TT genotype) and rs1799930 (AA genotype) associated with a higher risk of antituberculosis drug-induced hepatotoxicity [30]

rs1801279

rs1041983

rs1801280

rs1799929

rs1799930

rs1208

rs1799931

 113 Ghanaian Isoniazid doses and slow NAT2 genotype associated with Cmax and AUC0–8h of isoniazid. Twelve patients recorded Cmax isoniazid values<3 g/ml (low) and 49 recorded participants had Cmax values>6 g/ml (high). Of the 12 patients with low Cmax, only 1 had a rapid NAT2 genotype (wildtype homozygote) and 2 had a slow NAT2 genotype (variants homozygote). Of the 49 patients with high isoniazid, 26 had a slow NAT2 genotype (variants homozygote) [25]

NAT2*4

NAT2*5

NAT2*6

NAT2*7

NAT2*12

NAT2*13

NAT2*14

 30 Venezuelan AUC0-24 and t1/2 of isoniazid are statistically higher in slow acetylators (NAT2*5, *6, *7, *14) compared to genotypically rapid (NAT2*4, *12, *13) acetylators. Whereas the clearance was significantly lower in the slow acetylators compared with the rapid acetylators [31]

rs4646244, rs4646267

rs1799930, rs1799931

 221 Korean No association between NAT2 polymorphism with the antituberculosis drug-induced maculopapular eruption [32]
CYP2E1 rs2031920 408 Indian Could have the risk of antituberculosis drug-induced hepatotoxicity development [28]
rs2031920 2244 Uyghur No significant association between polymorphism and development of antituberculosis drug-induced hepatotoxicity [29]

rs2031920

rs6413432

 445 Chinese No significant association between polymorphism and development of antituberculosis drug-induced hepatotoxicity [33]

rs2031920, rs2070672

rs915908, rs8192775

rs2515641, rs2515644

 445 Chinese No significant association between polymorphism and development of antituberculosis drug-induced hepatotoxicity [34]

rs2031920, rs2070672

rs2070673

 221 Korean No association between CYP2E1 polymorphism with the antituberculosis drug-induced maculopapular eruption [32]
rs2031920 314 Indian Genotypic distribution of rs2031920 significantly higher in antituberculosis drug-induced hepatotoxicity than in the non-antituberculosis drug-induced hepatotoxicity group [35]

UGT1A1

UGT1A1, a gene in the UGT1A family, has been determined to code for UDP-glucuronosyltransferase. This enzyme catalyzes glucuronidation during phase II of drug metabolism, specifically conjugation. With it, various substances are processed, including estrogen, bilirubin, carcinogens, xenobiotics, and medications [11–13]. UGT1A1 is located on chromosome 2 at position 37.1 [36] (fig. 2).

Fig. 2: Cytogenetic location of UGT1A1 [37]

The presence of UGT1A1 polymorphism causes a decrease in enzyme activity, resulting in pharmacokinetic differences from drugs [14]. In Taipei, Taiwan, the UGT1A1 gene polymorphisms UGT1A1*27 (686C>A) and UGT1A1*28 [(TA)6→(TA)7] are associated with antituberculosis drug-induced hepatotoxicity (ATDIH) [19]. In Shanghai, China, polymorphisms in rs4148323 A/A genotypes significantly reduce the risk of developing ATDIH [20]. However, in other populations in China, studies located outside Shanghai found that polymorphisms at rs4148323 and rs8330 had no significant effect on the risk of developing ATDIH [21].

SLCO1B1

SLC (solute carrier family) is a transporter family that includes OATP [22, 23, 38]. This protein in hepatocytes facilitates hepatic uptake of compounds from the blood to be excreted [36]. In addition to transporting bile acids and other endogenous substances, OATP is also involved in the transportation of drugs [22, 23, 38]. OATP1B1 is an essential member of the OATP family and is found in the basolateral membrane of hepatocytes. Various drugs, including the first line anti TB drugs, rifampicin and rifabutin, are absorbed and transported via the hepatic portal system for uptake by OATP1B1, after which they will be metabolized and eliminated[38–40]. SLCO1B1, one of the genes that encode for the transporter, is situated in chromosome 12, in position 12.1[36] (fig. 3).

Genetic variations of this gene can change the activity of transporters, leading to drug pharmacokinetic changes [15, 16]. Gene variations from the haplotype analysis show that patients who have at least one SLCO1B1*15 haplotype have a higher risk of developing ATDIH compared to those who have a SLCO1B1*1a or SLCO1B1*1b haplotype in populations in Zhejiang, Guangxi, Chongqing, Jilin, China [22]. Other results have shown that patients with SCLO1B1 polymorphisms rs4149034 G/A and rs2900478 T/A have a lower risk of ATDIH. On the other hand, patients in Shanghai, China, with rs2417957 T/T and rs4149063 T/T have an increased risk of developing ATDIH [20]. In Korea, polymorphisms at rs4149013, rs4149014, rs2306283, and rs4149056 did not show an association with the risk of developing ATDIH [23]. In Ghanaian populations, patients with homozygous *1b variants (rs2306283) (AA genotype) significantly decreased the Cmax and AUC0–8h of rifampicin compared to the wildtype (GG genotype) [25]. Another study showed that rs4149032 and rs11045819 on Black African populations did not explain any variability in the AUC0–∞ of rifampin [24].

NAT2

NAT2 codes for enzymes that activate and deactivate drugs [17]. N-acetyltransferase is identified to be an enzyme mainly found in the liver to detoxify large amounts of chemical compounds. NAT2 has more than 23 variations to current knowledge [42s]. The polymorphism of this gene determines N-acetylation polymorphism, which can lead to fast, medium, and slow acetylator phenotypes. Polymorphism in this gene is also determined to be associated with cancer and higher drug toxicity [17]. NAT2 is on chromosome 8 at position 22 [43] (fig. 4).

Fig. 3: Cytogenetic location of SLCO1B1 [41]

Fig. 4: Cytogenetic location of NAT2 [43]

Based on several studies, polymorphisms of this gene are associated with the risk of developing ATDIH in TB patients. A polymorphism in rs1799930 in a TB patient has been found to be associated with an increased risk of developing ATDIH in Beijing [26], Indonesia [27], India [28], and Tunisia (AA genotype) [30]. In Tunisia, the GG genotype is associated with a decreased risk of ATDIH [30]. The rs1799931 gene polymorphism is associated with ATDIH in Beijing [26] and India [28]. Other polymorphisms at rs1041983 are associated with an increased risk of developing ATDIH in Beijing [26]. The rs1799929 gene polymorphism is associated with an increased risk of ATDIH in Indian [28], Tunisian (TT genotype) [30], and Xinjiang populations [29], while in Tunisian populations, the CC genotype was associated with a decreased risk of ATDIH [30]. Another study showed that rs1801279, rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 were associated with changes in the Cmax and AUC(0–8h) of isoniazid. Twelve patients recorded Cmax isoniazid values<3 g/ml (low), and 49 recorded participants had Cmax values>6 g/ml (high). Of the 12 patients with a low Cmax, only 1 was identified to have a rapid NAT2 genotype (wildtype homozygote), while 2 had a slow NAT2 genotype (variants homozygote). Of the 49 patients with high isoniazid Cmax, only 26 were determined to have a slow NAT2 genotype (variant homozygote) [25]. Meanwhile, in Venezuelan populations with the genotypes NAT2*4, *5, *6, *7, *12, *13, and *14, the AUC0–24 and t1/2 of isoniazid were statistically higher in slow acetylators (NAT2*5, *6, *7, *14) compared to genotypically rapid (NAT2*4, *12, *13) acetylators. Conversely, the clearance was significantly lower in the slow acetylators compared with the rapid acetylators [31]. In Korea, the NAT2 polymorphisms at rs4646244, rs4646267, rs1799930, and rs1799931 had no association with antituberculosis drug-induced maculopapular eruption [32].

CYP2E1

The CYP450 protein is a monooxygenase that catalyzes many of the reactions involved in drug metabolism. These enzymes metabolize endogenous or exogenous substrates [18]. CYP2E1 is one of the crucial enzymes in the metabolism of anti TB drugs, especially isoniazid. Several new studies were published regarding the relationship between CYP2E1 polymorphisms and ATDIH [26, 33, 44–46]. One of these studies describes how gene polymorphism coding for CYP2E1 can affect enzyme activity as well as susceptibility to hepatitis induced by anti-TB drugs [47].

In India, polymorphisms at rs2031920 have a significant associated risk of developing ATDIH [28]. In China, there were no significant relationships between rs2031920 [29, 33], rs2070672, rs915908, rs8192775, rs2515641, rs2515644 [34], and rs6413432 [33] with the risk of developing ATDIH. Another study showed that CYP2E1 polymorphism at rs2031920, rs2070672, and rs2070673 had no association with antituberculosis drug-induced maculopapular eruption in Korean populations [32]. In India, rs2031920 showed that significantly higher in antituberculosis drug-induced hepatotoxicity than in the non-antituberculosis drug-induced hepatotoxicity group [48].

In many of the studies above, genetic polymorphisms had an association with various anti TB drug responses, such as clearance, the risk of ATDIH, and the bioavailability of drugs (fig. 5), and can further lead to adverse outcomes.

Fig. 5: Effect of gene polymorphisms on the responses of antituberculosis drugs

CONCLUSION

There are several differences in gene polymorphisms in each population. Some genes that can affect the effectiveness and toxicity of antituberculosis drugs are UGT1A1, SLCO1B1, NAT2, and CYP2E1. Polymorphisms in these genes can cause harm to TB patients. In UGT1A1, polymorphisms at rs4148323 and rs8330 have no significant association with ATDIH; rs4148323 A/A could reduce ATDIH risk; UGT1A1*27 (686C>A) and UGT1A1*28 [(TA)6→(TA)7] could elevate ATDIH risk. In SLCO1B1, polymorphisms at rs4149034 G/A, rs1564370 G/C, and rs2900478 T/A are associated with a lower risk of ATDIH; rs2417957 T/T, rs4149063 T/T, and SLCO1B1*15 are related to a higher risk of ATDIH; rs4149013, rs4149014, rs2306283, rs4149056, and rs4149033 have no significant association with ATDIH; rs2306283 A/A significantly decreased Cmax and AUC0–8h of rifampicin; rs11045819 and rs414903 did not have a relationship with rifampicin's AUC0–∞. In NAT2, polymorphisms at rs1801280, rs1799930, 1799931, rs1041983, and rs1799929 are related to an increased the risk of ATDIH; rs1801279, rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 had observed variations in Cmax and AUC0–8h of isoniazid; rs4646244, rs4646267, rs1799930, and rs1799931 had no association with antituberculosis drug-induced maculopapular eruption. In CYP2E1, polymorphisms at rs3813867, rs2031920, rs6413432, rs2070672, rs915908, rs8192775, rs2515641, and rs2515644 had no significant relationship with the risk of developing ATDIH; rs2031920, rs2070672, and rs2070673 revealed no association with antituberculosis drug-induced maculopapular eruption. Therefore, personalized medicine that takes genetic polymorphisms into consideration is recommended in order to reach the optimal therapeutic result in each patient.

ACKNOWLEDGEMENT

None

FUNDING

Nil

AUTHORS CONTRIBUTIONS

All authors have contributed equally.

CONFLICT OF INTERESTS

Declared none

REFERENCES

  1. Houben RMGJ, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med 2016;13:1–13.

  2. Uplekar M, Weil D, Lonnroth K, Jaramillo E, Lienhardt C, Dias HM, et al. WHO’s new end TB strategy. Lancet 2015;385:1799–801.

  3. WHO. Moscow declaration ending tb in the sustainable development era; 2017. p. 1–8.

  4. Sun Q, Zhang Q, Gu J, Sun WW, 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;25:908–17.

  5. Setiawan SI, Ascobat P. Adverse reactions to first-line anti-tuberculosis drugs as a risk factor of pulmonary tuberculosis treatment default in Jakarta, Indonesia. Int J Appl Pharm 2019;11(Special Issue 6):80–3.

  6. Siddiqui S, Baig MMA, Jaffer S, Ansari SFR. Study on prevalence of adverse drug reactions in patients suffering from tuberculosis in a tertiary care hospital. Int J Pharm Pharm Sci 2016;8:375–7.

  7. Buntoro IF, Kristin E, Sumardi. Decrease of liver function after treatment of antituberculosis drugs in tuberculosis patients with malnutrition and alcohol consumption. Int J Pharm Pharm Sci 2016;8:269–73.

  8. Urban TJ, Goldstein DB, Watkins PB. Genetic basis of susceptibility to drug-induced liver injury: what have we learned and where do we go from here? Pharmacogenomics 2012;13:735–8.

  9. 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;190:1642–51.

  10. Kruglyak L, Nickerson DA. Variation is the spice of life. Nat Genet 2001;27:234–6.

  11. 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 2002;12:81-3.

  12. 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;60:950–6.

  13. 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 2007;7:333–8.

  14. Pacheco PR, Brilhante MJ, Ballart C, Sigalat F, Polena H, Cabral R, et al. UGT1A1, UGT1A6, and UGT1A7 genetic analysis. Mol Diagn Ther 2009;13:261–8.

  15. Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 2006;16:873–9.

  16. Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 2007;82:726–33.

  17. NCBI. NAT2 N-acetyltransferase 2; 2020. Available from: https://www.ncbi.nlm.nih.gov/gene/10 [Last accessed on 20 Jul 2020]

  18. NCBI. CYP2E1 cytochrome P450 family 2 subfamily E member 1; 2020. Available from: https://www.ncbi.nlm.nih.gov/ gene?cmd=Retrieveanddopt=full_reportandlist_uids=1571 [Last accessed on 20 Jul 2020]

  19. 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;16:376–8.

  20. 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 2017;37:1125–36.

  21. 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;20:812–8.

  22. 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;95:68–74.

  23. 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 2012;92:100–4.

  24. 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;61:1–9.

  25. 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. Antimicrob Agents Chemother 2018;62:1–11.

  26. 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;39:535–43.

  27. Yuliwulandari R, Susilowati RW, Wicaksono BD, Viyati K, Prayuni K, Razari I, et al. NAT2 variants are associated with the drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis. J Hum Genet 2016;61:533–7.

  28. Singla N, Gupta D, Birbian N, Singh J. Association of NAT2, GST and CYP2E1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity. Tuberculosis 2014;94:293–8.

  29. 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;9:1–8.

  30. 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 2012;60:324–30.

  31. 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;15:285–96.

  32. 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;67:121–7.

  33. 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;37:588–93.

  34. 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;8:1–7.

  35. 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;18:588–93.

  36. Charbonneau DH, Healy AM. Genetics home reference. J Consum Health Internet 2005;9:61–8.

  37. Genetics Home Reference. UGT1A1 gene; 2020. Available from: https://ghr.nlm.nih.gov/gene/UGT1A1#location [Last accessed on 20 Jul 2020]

  38. 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;60:617–20.

  39. 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;54:4192–200.

  40. 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.

  41. Genetics Home Reference. SLCO1B1 gene; 2020. Available from: https://ghr.nlm.nih.gov/gene/SLCO1B1#location [Last accessed on 20 Jul 2020].

  42. SNPedia. NAT2; 2020. Available from: https:// www.snpedia.com/index.php/NAT2 [Last accessed on 20 Jul 2020].

  43. Genetics Home Reference. NAT2 gene; 2020. Available from: https://ghr.nlm.nih.gov/gene/NAT2#location [Last accessed on 20 Jul 2020].

  44. Teixeira RL de F, Renata Gomes Morato PHC, Muniz LMK, Moreira A da SR, Afrânio Lineu Kritski FCQM, Suffys PN, 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;106:716–24.

  45. 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;14:622–6.

  46. 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;38:977–86.

  47. 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;37:924–30.

  48. 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 2014;2:439–49.