NAT2 Gene Polymorphisms and Plasma Isoniazid Concentration in Vietnamese Tuberculosis Patients
Keywords:N-acetyltransferase 2 enzyme, NAT2 polymorphisms, Isoniazid, Tuberculosis
Isoniazid (INH) is one of the most common drugs for tuberculosis (TB) treatment and INH acetylation catalyzed by non-inducible hepatic enzyme arylamine N-acetyltransferase type 2 (NAT2). The isoniazid acetylation rates, which depend on NAT2 genotypes, is constant in an individual but can changes between patients. Phenotypic groups can be classified based on the genotype: slow, intermediate, and rapid acetylators. This study was performed to identify the relation between NAT2 gene polymorphisms and plasma INH concentrations among the different genotypes of Vietnamese tuberculosis patients. Blood samples of 136 adult TB patients treated with INH were collected and genotyped for NAT2 gene polymorphisms using Sanger sequencing. Two-hour post-dosing INH plasma concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). Among the 136 patients genotyped, there were 43 (31.62 %), 58 (42.65 %), and 35 (25.74 %) of slow, intermediate, and rapid acetylation phenotypes, with two-hour post dosing INH plasma concentrations of 3.4, 2.7, and 2.2 μg/ml, respectively. The differences in INH concentrations among the three genotypes were significant (P < 0.05). Genotyping of TB patients from Vietnam for NAT2 gene polymorphism revealed that 48 percent of the study population comprised slow acetylators. Two-hour INH levels were significantly different among CC and TT homozygous genotypes of NAT2(C282T), as 2.7 μg/ml and 3.9 μg/ml, respectively. This suggests that NAT2(C282T) could play a role in INH metabolism in TB patients.
Methods: Blood samples of 136 adult TB patients treated with INH were collected and genotyped for NAT2 gene polymorphisms using Sanger sequencing. Two-hour post-dosing INH plasma concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS).
Results: Among the 136 patients genotyped, there were 43 (31.62%), 58 (42.65%) and 35 (25.74%) of slow, intermediate and rapid acetylation phenotypes with two-hour post dosing INH plasma concentration of 3.4, 2.7 and 2.2 μg/ml, respectively. The differences in INH concentrations among the three genotypes were significant (P<0.05).
Conclusions: Genotyping of TB patients from Vietnam for NAT2 gene polymorphism revealed that 48 per cent of the study population comprised slow acetylators. Two-hour INH levels were significantly different among slow and rapid acetylators.
World Health Organization. Global Tuberculosis Report 2018. World Health Organization, Geneva, Switzerland, 2018.
H Mclleron and M Chirehwa. Current research toward optimizing dosing of first-line antituberculosis treatment. Expert Rev. Anti Infect. Ther. 2018; 17, 27-38.
A Zabost, S Brzezinska, M Kozinska, M Blachnio, J Jagodzinski, Z Zwolska and E Augustynowicz-Kopec. Correlation of N-acetyltransferase 2 genotype with isoniazid acetylation in Polish tuberculosis patients. Biomed. Res. Int. 2013; 2013, 853602.
P Wang, K Pradhan, XB Zhong and X Ma. Isoniazid metabolism and hepatotoxicity. Acta Pharm. Sin. B 2016; 6, 384-92.
J Azuma, M Ohno, R Kubota, S Yokota, T Nagai, K Tsuyuguchi, Y Okuda, T Takashima, S Kamimura, Y Fujio and I Kawase. NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy. Eur. J. Clin. Pharmacol. 2013; 69, 1091-101.
JM Walraven, Y Zang, JO Trent and DW Hein. Structure/function evaluations of single nucleotide polymorphisms in human N-acetyltransferase 2. Curr. Drug. Metab. 2008; 9, 471-86.
M Zhang, S Wang, B Wilffert, R Tong, DV Soolingen, SVD Hof and JW Alffenaar. The association between the NAT2 genetic polymorphisms and risk of DILI during anti-TB treatment: A systematic review and meta-analysis. Br. J. Clin. Pharmacol. 2018; 84, 2747-60.
IB Kuznetsov, M McDuffie and R Moslehi. A web server for inferring the human N-acetyltransferase-2 (NAT2) enzymatic phenotype from NAT2 genotype. Bioinformatics 2009; 25, 1185-6.
R Weinshilboum. Inheritance and drug response. N. Engl. J. Med. 2003; 348, 529-37.
TL Le, MH Ta, TH Le, AT Le, TLH Duong, VD Hoang and TT Bui. Simultaneous determination of pyrazinamide, rifampicin, ethambutol, isoniazid and acetyl isoniazid in human plasma by LC-MS/MS method. J. Appl. Pharmaceut. Sci. 2019; 8, 61-73.
J Yoo, Y Lee, Y Kim, SY Rha and Y Kim. SNPAnalyzer 2.0: A web-based integrated workbench for linkage disequilibrium analysis and association analysis. BMC Bioinformat. 2008; 9, 290.
A Sabbagh, P Darlu, A Langaney and ES Poloni. Haplotype tagging efficiency and tagSNP sets portability in worldwide populations in NAT2 gene. Bulletins et Mémoires de la Société d’Anthropologie de Paris 2007; 19, 1-9.
B Chen, JH Li, YM Xu, J Wang and XM Cao. The influence of NAT2 genotypes on the plasma concentration of isoniazid and acetylisoniazid in Chinese pulmonary tuberculosis patients. Clin. Chim. Acta 2006; 365, 104-8.
GA Ellard. Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis. Clin. Pharmacol. Ther. 1976; 19, 610-25.
M Kinzig-Schippers, D Tomalik-Scharte, A Jetter, B Scheidel, V Jakob, M Rodamer, I Cascorbi, O Doroshyenko, F Sorgel and U Fuhr. Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses? Antimicrob. Agents Chemother. 2005; 49, 1733-8.
N Singh, S Dubey, S Chinnaraj, A Golani and A Maitra. Study of NAT2 gene polymorphisms in an Indian population: Association with plasma isoniazid concentration in a cohort of tuberculosis patients. Mol. Diagn. Ther. 2009; 13, 49-58.
R Kubota, M Ohno, T Hasunuma, H Iijima and J Azuma. Dose-escalation study of isoniazid in healthy volunteers with the rapid acetylator genotype of arylamine N-acetyltransferase 2. Eur. J. Clin. Pharmacol. 2007; 63, 927-33.
G Ramachandran and S Swaminathan. Role of pharmacogenomics in the treatment of tuberculosis: A review. Pharmgenom. Pers. Med. 2012; 5, 89-98.
A Alsultan and CA Peloquin. Therapeutic drug monitoring in the treatment of tuberculosis: An update. Drugs 2014; 74, 839-54.
AK Hemanth Kumar, K Ramesh, T Kannan, V Sudha, H Haribabu, J Lavanya, S Swaminathan and G Ramachandran. N-acetyltransferase gene polymorphisms & plasma isoniazid concentrations in patients with tuberculosis. Indian J. Med. Res. 2017; 145, 118-23.
World Health Organization. Companion Handbook to the WHO Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis. World Health Organization, Geneva, Switzerland, 2014.
JA Jung, TE Kim, H Lee, BH Jeong, HY Park, K Jeon, OJ Kwon, JW Ko, R Choi, HI Woo, WJ Koh and SY Lee. A proposal for an individualized pharmacogenetic-guided isoniazid dosage regimen for patients with tuberculosis. Drug Des. Devel. Ther. 2015; 9, 5433-8.
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