Investigation of the Relationship between the Multidrug Resistance 1 Gene Polymorphisms and Bronchodilator Response in COPD

Year 2024, , 28 - 33, 30.05.2024

Ersan Atahan , Buket Çalışkaner Öztürk , Suat Sarıbaş , Bülent Tutluoğlu

https://doi.org/10.26650/EurJBiol.2024.1330850

Abstract

Objective: Chronic obstructive pulmonary disease (COPD) is described as partially reversible airflow limitation. P-glycoprotein (P-gp/MDR1), encoded by the Multidrug Resistance 1 (MDR1) gene, is regarded as a protective component for the respiratory tract and is present in tracheobronchial epithelium and lung parenchyma, and removes particles from cells and protects against various xenobiotics. Polymorphisms of MDR1 gene and the alteration in the expression of P-gp are considered to have a negative effect on the severity of COPD pathogenesis and treatment efficacy. We aimed to investigate the relationship of the MDR1 gene polymorphisms with reversibility in COPD patients.
Materials and Methods: The MDR1 polymorphisms, specifically the 3435C>T and 2677A/G variations, were analyzed in 90 COPD patients.
Results: 15 of the 90 COPD patients had positive reversibility tests. 2677TT (p=0.044) and 3435TT (p=0.003) alleles related to positive reversibility tests. There were no significant differences in the distribution of the MDR1 C3435 alleles and the G2677 alleles (p> 0.05).
Conclusion: COPD patients with the TT allele have a higher rate of early reversibility positivity; this suggests that those carrying the allele may respond better to bronchodilator therapy. These markers could help to distinguish COPD patients who respond better to β2-agonists or who may not benefit much and, therefore, need different drugs.

Keywords

COPD, MDR1, polymorphism

References

• Mathers CD, Loncar D. Projections of global mortality and bur-den of disease from 2002 to 2030. PLoS Med. 2006;3(11):e442. doi: 10.1371/journal.pmed.0030442. google scholar
• Global strategy for the diagnosis, management, and pre-vention of chronic obstructive pulmonary disease (updated 2022). GOLD. Available from: https://goldcopd.org/wp-content/uploads/2019/12/GOLD-2020-FINAL-ver1.2-03Dec19_WMV.pdf google scholar
• Hamilton KO, Yazdanian MA, Audus KL. Contribution of efflux pump activity to the delivery of pulmonary therapeutics. Curr Drug Metab. 2002;3(1):1-12. google scholar
• Lechapt-Zalcman E, Hurbain I, Lacave R, et al. MDR1-Pgp 170 expression in human bronchus. Eur Respir J. 1997;10(8):1837-1843. google scholar
• Scheffer GL, Pijnenborg AC, Smit EF, et al. Multidrug resistance related molecules in human and murine lung. J Clin Pathol. 2002;55(5):332-339. google scholar
• Hoffmeyer S, Burk O, von Richter O, et al. Functional poly-morphisms of the human multidrug-resistance gene: multi-ple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA. 2000;97(7):3473-3478. google scholar
• Cascorbi I, Gerloff T, Johne A, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug trans-porter MDR1 gene in white subjects. Clin Pharmacol Ther. 2001;69(3):169-174. google scholar
• Tang K, Wong LP, Lee EJ, Chong SS, Lee CG. Genomic ev-idence for recent positive selection at the human MDR1 gene locus. Hum Mol Genet. 2004;13(8):783-797. google scholar
• Lehmann S, Bakke PS, Eide GE, Humerfelt S, Gulsvik A. Bronchodilator reversibility testing in an adult general popu-lation; the importance of smoking and anthropometrical vari-ables on the response to a beta2-agonist. Pulm Pharmacol Ther. 2006;19(4):272-280. google scholar
• Schermer T, Hejdra Y, Zadel S, et al. Flow and volume re-sponses after routine salbutamol reversibility testing in mild to very severe COPD. Respir Med. 2007;101(6):1355-1362. google scholar
• Miller M, Ramsdell J, Friedman PJ, Cho JY, Renvall M, Broide DH. Computed tomographic scan-diagnosed chronic obstructive pulmonary disease-emphysema: Eotaxin-1 is associated with bronchodilator response and extent of emphysema. J Allergy Clin Immunol. 2007;120(5):1118-1125. google scholar
• Izzotti A, Cartiglia C, Longobardi M, et al. Alterations of gene expression in skin and lung of mice exposed to light and cigarette smoke. FASEB J. 2004;18(13):1559-1561. google scholar
• Milojkovic M, Milacic N, Radovic J, Ljubisavljevic S. MDR1 gene polymorphisms and P-glycoprotein expression in respi-ratory diseases. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015;159(3):341-346. google scholar
• Ishikawa T, Hirano H, Onishi Y, Sakurai A, Tarui S. Func-tional evaluation of ABCB1 (P-glycoprotein) polymorphisms: High-speed screening and structure-activity relationship analy-ses. Drug Metab Pharmacokinet. 2004;19(1):1-14. google scholar
• Schwab M, Eichelbaum M, Fromm MF. Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol. 2003;43:285-307. google scholar
• Papp E, Gadawski I, Cöte HC. Longitudinal effects of thymi-dine analogues on mtDNA, mtRNA and multidrug resistance (MDR-1) induction in cultured cells. J Antimicrob Chemother. 2008;61(5):1048-1052. google scholar
• Israeli D, Ziaei S, Gonin P, Garcia L. A proposal for the physio-logical significance of mdr1 and Bcrp1/Abcg2 gene expression in normal tissue regeneration and after cancer therapy. J Theor Biol. 2005;232(1):41-45. google scholar
• van der Deen M, Marks H, Willemse BW, et al. Diminished ex-pression of multidrug resistance-associated protein 1 (MRP1) in bronchial epithelium of COPD patients. Virchows Arch. 2006;449(6):682-688. google scholar
• Gümüş-Akay G, Rüstemoğlu A, Karadağ A, Sunguroğlu A. Genotype and allele frequencies of MDR1 gene C1236T polymorphism in a Turkish population. Genet Mol Res. 2008;7(4):1193-1199. google scholar
• Dogan OT, Katrancioglu N, Karahan O, Sanli GC, Zorlu A, Manduz S. Frequency of the mdr-1 C>T gene polymorphism in patients with COPD. Clinics (Sao Paulo). 2010;65(11):1115-1117. google scholar
• Toru U, Ayada C, Genç O, Turgut S, Turgut G, Bulut I. MDR-1 gene C/T polymorphism in COPD: Data from Aegean part of Turkey. IntJ Clin Exp Med. 2014;7(10):3573-3577. google scholar
• Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A "silent" polymor-phism in the MDR1 gene changes substrate specificity. Science. 2007;315(5811):525-528. google scholar
• Zhang X, Mahmudi-Azer S, Connett JE, et al. Association of Hck genetic polymorphisms with gene expression and COPD. Hum Genet. 2007;120(5):681-690. google scholar
• Hizawa N, Makita H, Nasuhara Y, et al. Beta2-adrenergic recep-tor genetic polymorphisms and short-term bronchodilator re-sponses in patients with COPD. Chest. 2007;132(5):1485-1492. google scholar
• Toru U, Ayada C, Genç O, Turgut S, Turgut G, Bulut I. MDR-1 gene C/T polymorphism in COPD: Data from Aegean part of Turkey. IntJ Clin Exp Med. 2014;7(10):3573-3577. google scholar
• Chernetska NV, Stupnytska HY, Fediv OI. The role of MDR1 (C3435T) gene polymorphism in patients with chronic obstruc-tive pulmonary disease associated with type 2 diabetes mellitus. J Med Life. 2020;13(3):349-355. google scholar