The effect of Polymorphism of the MDR1 (ABCB1) Gene on the Risk of Hepatotoxic Reactions in Patients with Pulmonary Tuberculosis

Currently, a decrease is seen in the effectiveness of treatment in patients with tuberculosis due to the appearance of adverse reactions to anti-tuberculosis drugs. Hepatotoxic reactions play an especially important role in anti-tuberculosis therapy, and phthisiologists often have to deal with the cancellation of a number of anti-tuberculosis drugs. The aim of the study was to investigate the relationship of polymorphic gene variants of xenobiotic biotransformation metabolizing enzymes (NAT2 (590G>A (rs1799930), CYP2E1 (9896C>G (rs2070676), ABCB1 (3435T>C (rs1045642), GSTM1 (E/D), GSTT1 (E/D) with the risk of hepatotoxic reactions in patients with pulmonary tuberculosis. Material and methods. The logistic regression analysis method was used to predict the probability of hepatoxic reactions during specific anti-tuberculosis therapy. Results: 1 statistically significant model was obtained, which reflects the association with hepatotoxic reactions to anti-tuberculosis drugs of the TS genotypes or the TS gene (T allele) ABSV1 (rs1045642). Conclusion. Pharmacogenetic testing used in the study allows us to identify risk groups of patients with pulmonary tuberculosis according to the likelihood of hepatotoxic reactions, which may provide an individualized approach to the treatment of these patients in the future.

1. Afanasyev E.I., Russkikh O.E. Modern trends in the epidemiology of tuberculosis and HIV infection in the world and in the Russian Federation. Russian International Journal. 2021; 3: 24–26. (in Russian)

2. Vasilyeva I.A., Belilovsky E.M., Borisov S.E. etc. Global reports of the World Health Organization on Tuberculosis. Formation and interpretation. Tuberculosis and Lung Diseases. 2017; 95 (5): 7–16. (in Russian)

3. Ivanova D.A., Borisov E.E. Spectrum and risk factors of undesirable adverse reactions in the treatment of patients with pulmonary tuberculosis. Tuberculosis and Lung Diseases. 2017; 95 (6): 22–29. (in Russian)

4. Kazakov A.V., Mozhokina G.N., Aksenova V.A. Effect of genetic polymorphism of the enzyme genes responsible for biotransformation of antituberculous drug on the risk of hepatotoxic reaction in patients with tuberculosis. Antibiotiki i Khimioter = Antibiotics and Chemotherapy. 2018; 63 (5–6): 20–25. (in Russian)

5. Galkina K.Yu. Determination of the type of acetylation in patients with pulmonary tuberculosis. Scientific works: to the 80th anniversary of the birth of Academician V.I. Litvinov of the Russian Academy of Medical Sciences. Moscow: 2021; 543–553. (in Russian)

6. Sokolova G. B. Individualized chemotherapy of pulmonary tuberculosis (experimental clinical study): Dis. ... Doctor of Medical Sciences, in the form of a scientific report. — M.: 2000. (in Russian)

7. Wang D., Johnson A.D., Papp A.C., Kroetz D.L., Sadée W. Multidrug resistance polypeptide 1 (MDR 1, ABCB 1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics. 2005; 15(10): 693–704).

8. Mooij M.G., Nies A.T., Knibbe C.A., Schaeffeler E., Tibboel D., Schwab M. et al. Development of human membrane transporters: drug disposition and pharmacogenetics. Clin Pharmacokinet. 2016; 55 (5): 507–24. doi: 10.1007/s40262-015-0328-5.

9. Cai Y., Yi J., Zhou C., Shen X. 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. doi: 10.1371/journal.pone.0047769.

10. Canaparo R., Finnstrom N., Serpe L. et al. Expression of CYP3A isoforms and P-glycoprotein in human stomach, jejunum and ileum. Clin Exp Pharmacol Physiol. 2007 Nov; 34 (11): 1138–1144. doi: 10.1111/j.1440- 1681.2007.04691.x.

11. Belmonte C., Ochoa D., Roman M., Saiz-Rodriguez M., Wojnicz A., GomezSanchez C.I. et al. Influence of CYP2D6, CYP3A4, CYP3A5 and ABCB1 polymorphisms on pharmacokinetics and safety of aripiprazole in healthy volunteers. Basic Clin Pharmacol Toxicol. 2018; 122 (6): 596–605. doi: 10.1111/bcpt.12960. Epub 2018 Feb 22.

12. Polonikov A.V. Polymorphism of genes of xenobiotic biotransformation enzymes and their complex effect on predisposition to multifactorial diseases: diss...Doctors of Medical Sciences: 03.00.15. Moscow: 2006' 442. (in Russian)

13. Pavlova E.N., Erokhina M.V., Rybalkina E.Yu., etc. The effect of rifampicin on the induction of MDR1/P-gp activity in human proinflammatory macrophages. Antibiotiki i Khimioter = Antibiotics and Chemotherapy. 2022; 67 (3–4): 16–22. doi: https://doi.org/10.37489/0235-2990-2022- 67-3-4-16-22. (in Russian)