ISONIAZID-INDUCED LIVER INJURY: PHARMACOGENETIC ASPECTS
https://doi.org/10.18705/2782-3806-2022-2-3-38-46
Abstract
Inter-individual differences in anti-tuberculosis chemotherapy outcomes have been demonstrated in clinical practice, such as, achievement of intended therapeutic effect in some patients, and insufficiency or absence of response to treatment in others, with development of adverse drug reactions, especially, isoniazid-induced liver injury. Isoniazid-induced liver injuries are the main reason for isoniazid discontinuation, which further leads to considerably reduced effectiveness of anti-tuberculosis chemotherapy, increased relapse risk, and secondary drug-resistance of M. tuberculosis. Hepatotoxic reactions to chemotherapy are predicated by mutations in genes encoding enzymes participating in isoniazid biotransformation: N-acetyltransferase 2 (NAT2), cytochrome P450 2Е1, and glutathione-S-transferase.
NAT2 gene polymorphism has been identified as risk factor for isoniazid hepatotoxicity. Nucleotide substitutions in NAT2 gene cause modification of enzyme protein structure, reduction of enzyme synthesis and alteration of its activity. Based on genetically-determined isoniazid acetylation rate, patients are referred to three acetylator types: rapid, intermediate, and slow. Correlations have been established in meta-reviews and systematic reviews between slow acetylator type and frequency of hepatotoxic reactions to isoniazid.
Based on study findings, interrelation was shown between cytochrome P450 CYP2E1 gene polymorphism and increased risk of liver injury during chemotherapy with isoniazid. Contribution of GSTM1 and GSTT1 genotypes to isoniazid toxicity requires further exploration, as the obtained results were ambiguous and controversial.
About the Authors
N. M. Krasnova
M. K. Ammosov North-Eastern Federal University, Medical Institute
Russian Federation
Russian Federation
Krasnova Natalia M., Candidate of Medical Sciences, Associate Professor of the Medical Institute
Belinsky str., 58, Yakutsk, 677000
V. M. Nikolaev
Yakutsk Scientific Center for Complex Medical Problems
Russian Federation
Russian Federation
Nikolaev Vyacheslav M., PhD, Senior Researcher at the Department of Epidemiology of Chronic Non-Communicable Diseases
Yakutsk
References
1. Клинические рекомендации «Туберкулез у взрослых» (2022), утвержденные Минздравом России. https://cr.minzdrav.gov.ru/recomend/16_2 (дата обращения 10.04.2022).
2. Wang P, Pradhan K, Zhong XB, et al. Isoniazid metabolism and hepatotoxicity. Acta Pharm Sin B. 2016;6(5):384–392. DOI:10.1016/j.apsb.2016.07.014.
3. Erwin ER, Addison AP, John SF, et al. Pharmacokinetics of isoniazid: The good, the bad, and the alternatives. Tuberculosis (Edinb). 2019;116(l):66–70. DOI:10.1016/j.tube.2019.04.012.
4. Klein DJ, Boukouvala S, McDonagh EM, et al. PharmGKB summary: isoniazid pathway, pharmacokinetics. Pharmacogenet Genomics. 2016;26(9):436–444. DOI:10.1097/FPC.0000000000000232.
5. Snalina NE., Sychev DA. Genetic predictors of isoniazid hepatotoxicity. Molecular Medicine 2018;16(2):31–36. DOI:10.29296/24999490-2018-02-04. In Russian
6. Khan SR, Morgan AG, Michail K, et al. Metabolism of isoniazid by neutrophil myeloperoxidase leads to isoniazid-NAD+ adduct formation: a comparison of the reactivity of isoniazid with its known human metabolites. Biochemical Pharmacology. 2016;106:46–55. DOI:10.1016/j.bcp.2016.02.003.
7. Jarrar YB, Balasmeh AA, Jarrar W. Sequence analysis of the N-acetyltransferase 2 gene (NAT2) among Jordanian volunteers. Libyan J Med. 2018;13(1):1408381. DOI:10.1080/19932820.2017.1408381.
8. Khan S, Mandal RK, Elasbali AM, et al. Pharmacogenetic association between gene polymorphisms and isoniazid induced hepatotoxicity: trial sequence meta-analysis as evidence. Biosci Rep. 2019;39(1). DOI:10.1042/BSR20180845.
9. Walraven JM., Zang Yu, et al. Structure/Function Evaluations of Single Nucleotide Polymorphisms in Human N-Acetyltransferase 2. Curr Drug Metab. 2008;9(6):471–486. DOI:10.2174/138920008784892065.
10. Zhu R, Kiser JJ, Seifart HI, et al. The pharmacogenetics of NAT2 enzyme maturation in perinatally HIV exposed infants receiving isoniazid. J Clin Pharmacol. 2012;52(4):511–519. DOI:10.1177/0091270011402826.
11. Zabost A, Brzezińska S, Kozińska M, et al. Correlation of N-Acetyltransferase 2 Genotype with Isoniazid Acetylation in Polish Tuberculosis Patients. Biomed Res Int. 2013; 2013:853602. DOI:10.1155/2013/853602.
12. Yadav D, Kumar R, Dixit RK, et al. Association of NAT2 gene polymorphism with antitubercular druginduced hepatotoxicity in the Eastern Uttar Pradesh population. Cureus. 2019;11(4):e4425. DOI:10.7759/cureus.4425.
13. Prikladnaya farmakogenetika: Monografiya. Pod redaktsiei D. A. Sycheva. Tver’: Triada, 2021. P. 496. In Russian
14. Peretolchina NP, Malov IV, Seminskiy IZh. Role of N-acetyltransferase 2 gene polymorphism in the human pathology. Acta biomedica scientifica. 2021;6(5):30–43. DOI:10.29413/ABS.2021-6.5.4 In Russian
15. Metushi I, Uetrecht J, Phillips E. Mechanism of isoniazid-induced hepatotoxicity: then and now. Br J Clin Pharmacol. 2016;81(6):1030–1036. DOI:10.1111/bcp.12885.
16. Boelsterli UA, Lee KK. Mechanisms of isoniazid-induced idiosyncratic liver injury: emerging role of mitochondrial stress. J Gastroenterol Hepatol. 2014;29(4):678–87. DOI:10.1111/jgh.12516.
17. Hassan HM, Guo HL, Yousef BA. Hepatotoxicity mechanisms of isoniazid: A mini-review. J Appl Toxicol. 2015;35(12):1427–1432. DOI:10.1002/jat.3175.
18. Nanashima K, Mawatari T, Tahara N, et al. Genetic variants in antioxidant pathway: risk factors for hepatotoxicity in tuberculosis patients. Tuberculosis (Edinb). 2012;92(3):253–259. DOI:10.1016/j.tube.2011.12.004.
19. Hussain SM, Frazier JM. Cellular toxicity of hydrazine in primary rat hepatocytes. Toxicol Sci. 2002;69(2):424–432. DOI:10.1093/toxsci/69.2.424.
20. Ghatineh S, Morgan W, Preece NE, et al. A biochemical and NMR spectroscopic study of hydrazine in the isolated rat hepatocyte. Arch Toxicol. 1992;66(9):660–668. DOI:10.1007/BF01981506.
21. Lee KK, Fujimoto K, Zhang C, et al. Isoniazidinduced cell death is precipitated by underlying mitochondrial complex I dysfunction in mouse hepatocytes. Free Radic Biol Med. 2013;65:584–594. DOI:10.1016/j.freeradbiomed.2013.07.038.
22. Metushi IG, Cai P, Zhu X, et al. A fresh look at the mechanism of isoniazid-induced hepatotoxicity. Clin Pharmacol Ther. 2011;89(6):911–914. doi:10.1038/clpt.2010.355.
23. Meng X, Maggs JL, Usui T, et al. Auto-oxidation of Isoniazid Leads to Isonicotinic-Lysine Adducts on Human Serum Albumin. Chem Res Toxicol. 2015;28(1):51–58. DOI:10.1021/tx500285k.
24. Metushi IG, Lee WM, Uetrecht J. IgG3 is the dominant subtype of anti-isoniazid antibodies in patients with isoniazid-induced liver failure. Chem Res Toxicol. 2014;27(5):738–740. DOI:10.1021/tx500108u.
25. O’Connor, Brady MF. Isoniazid Courtney In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan.
26. Kachanova AA, Pimenova YuA, Shuev GN, et al Study of the effect of polymorphic markers of the NAT2 gene on the risk of adverse drug reactions in patients with pulmonary tuberculosis who received isoniazid and rifampicin. Bezopasnost’ i risk farmakoterapii = Safety and Risk of Pharmacotherapy. 2021;9(1):25–33. DOI:10.30895/2312-7821-2021-9-1-25-33. In Russian
27. Suvichapanich S, Fukunaga K, Zahroh H, et al. NAT2 ultraslow acetylator and risk of anti-tuberculosis drug-induced liver injury: a genotype-based metaanalysis. Pharmacogenet Genomics. 2018;28(7):167–176. DOI:10.1097/FPC.0000000000000339.
28. Zhang M, Wang S, Wilffert B, et al. 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(12):2747–2760. DOI:10.1111/bcp.13722.
29. Lei S, Gu R, Ma X. Clinical perspectives of isoniazidinduced liver injury. Liver Research.2021;5(2):45–52. DOI:10.1016/j.livres.2021.02.001.
30. Sotsuka T, Sasaki Y, Hirai S, et al. Association of isoniazid-metabolizing enzyme genotypes and isoniazidinduced hepatotoxicity in tuberculosis patients. In Vivo. Sep-Oct 2011;25(5):803–12.
31. Yang S, Hwang SJ, Park JY, et al. Association of genetic polymorphisms of CYP2E1, NAT2, GST and SLCO1B1 with the risk of anti-tuberculosis drug-induced liver injury: a systematic review and meta-analysis. BMJ Open. 2019;9(8):e027940. Published 2019 Aug 1. DOI:10.1136/bmjopen-2018-027940.
32. Stepanova NA, Galimzyanov KM, Kantemirova BI. Intoxication syndrome in patients with pulmonary tuberculosis in relation to the system glutathione transferase gene polymorphism. Journal Infectology. 2017;9(2):13–16. DOI:10.22625/2072-6732-2017-9-2-13-16. In Russian.
33. Pourkeramati A, Zare Mehrjardi E, Dehghan Tezerjani M, et al. Association of GSTP1, GSTT1 and GSTM1 Gene Variants with Coronary Artery Disease in Iranian Population: A Case-Control Study. Int J Gen Med. 2020;13:249–259. Published 2020 May 28. DOI:10.2147/IJGM.S252552.
34. Leiro V, Fernández-Villar A, Valverde D, et al. Influence of glutathione S-transferase M1 and T1 homozygous null mutations on the risk of antituberculosis drug-induced hepatotoxicity in a Caucasian population. Liver Int. 2008;28(6):835–839. DOI:10.1111/j.1478-3231.2008.01700.x.
Review
For citations:
Krasnova N.M., Nikolaev V.M. ISONIAZID-INDUCED LIVER INJURY: PHARMACOGENETIC ASPECTS. Russian Journal for Personalized Medicine. 2022;2(3):38-46. (In Russ.) https://doi.org/10.18705/2782-3806-2022-2-3-38-46
Views:
1237
Email this article 