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Drug Res (Stuttg) 2020; 70(08): 341-347
DOI: 10.1055/a-1185-8762
Original Article

Comparative Study of the Effect of Macrolide Antibiotics Erythromycin, Clarithromycin, and Azithromycin on the ERG1 Gene Expression in H9c2 Cardiomyoblast Cells

Nima Hajimirzaei
1   Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
,
Nazila Pour Khalili
2   Center for Cell Pathology Research, Department of Biological Sciences, Khazar University, Baku, Azerbaijan
,
Behshad Boroumand
1   Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
,
Fatemeh Safari
3   Department of Physiology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
,
Armin Pourhosseini
1   Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
,
Reza Judi-Chelan
4   Department of Maxillofacial surgery, Shahid Rahnemun Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
,
Fatemeh Tavakoli
1   Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Abstract

Macrolides are clinically well-established class of antibiotics. Macrolides induce cardiotoxicity by blocking ether-a-go-go–related gene (ERG) potassium channels in cardiac myocytes. The aim of this study was to compare the effects of erythromycin, clarithromycin and azithromycin on cell viability and expression of ERG1 gene in H9c2 cells. Cell viability and ERG1 gene expression of H9c2 cells in 3 different concentrations, 1, 10 and 25 µg/ml, after 48 and 72 h were determined by MTT test and Real time-PCR method respectively. After 48 h, the growth of H9c2 cells treated with erythromycin, clarithromycin and Azithromycin (except two doses) were inhibited significantly compared to control group (p<0.05). All three groups of antibiotics showed toxic effects on cells after 72 h in all concentrations. Azithromycin-inhibiting effects were significantly higher than two other groups after 72 h of treatment. The expression of ERG1 gene increased in all three groups of antibiotics by increasing the concentration and duration of treatment. Azithromycin had the most pronounced effect on ERG1 expression in 48 and 72 h. This study indicated that these macrolides affect ERG1 expression due to their potential cardiac adverse effects. Further investigations are required to understand the exact mechanism of cardiotoxicity associated with macrolides.

Key words

adverse drug reactions - antibacterial drugs - cardiovascular pharmacology - K-channels - molecular pharmacology - toxicology


Publication History

Received: 02 April 2020

Accepted: 18 May 2020

Article published online:
19 June 2020

© Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Salimi A, Eybagi S, Seydi E. et al. Toxicity of macrolide antibiotics on isolated heart mitochondria: A justification for their cardiotoxic adverse effect. Xenobiotica 2016; 46: 82-93
    CrossrefPubMedSearch in Google Scholar
  • 2 Kwiatkowska B, Maślińska M. Macrolide therapy in chronic inflammatory diseases. Mediators Inflamm 2012; 636157
    PubMedSearch in Google Scholar
  • 3 Gerber MA, Baltimore RS, Eaton CB. et al. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: A scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: Endorsed by the American Academy of Pediatrics. Circulation 2009; 119: 1541-1551
    CrossrefPubMedSearch in Google Scholar
  • 4 Cyphert EL, Wallat JD, Pokorski JK. et al. Erythromycin modification that improves its acidic stability while optimizing it for local drug delivery. Antibiotics 2017; 6: 11
    CrossrefPubMedSearch in Google Scholar
  • 5 Labro MT. Macrolide antibiotics: current and future uses. Expert Opin Pharmacother 2004; 5: 541-550
    CrossrefPubMedSearch in Google Scholar
  • 6 Takahashi S, Kiyota H, Ito S. et al. Clinical efficacy of a single two gram dose of azithromycin extended release for male patients with urethritis. Antibiotics 2014; 3: 109-120
    CrossrefPubMedSearch in Google Scholar
  • 7 Jelić D, Antolović R. From erythromycin to azithromycin and new potential ribosome-binding antimicrobials. Antibiotics 2016; 5: 29
    CrossrefPubMedSearch in Google Scholar
  • 8 Vázquez-Laslop N, Mankin AS. How macrolide antibiotics work. Trends Biochem Sci 2018; 43: 668-684
    CrossrefPubMedSearch in Google Scholar
  • 9 Svanström H, Pasternak B, Hviid A. Use of clarithromycin and roxithromycin and risk of cardiac death: Cohort study. BMJ 2014; 349: 4930
    PubMedSearch in Google Scholar
  • 10 Li X, Wang M, Liu G. et al. Macrolides use and the risk of sudden cardiac death. Expert Rev Anti Infect Ther 2016; 14: 535-537
    CrossrefPubMedSearch in Google Scholar
  • 11 Guo D, Cai Y, Chai D. et al. The cardiotoxicity of macrolides: A systematic review. Pharmazie 2010; 65: 631-640
    PubMedSearch in Google Scholar
  • 12 Giudicessi JR, Ackerman MJ. Azithromycin and risk of sudden cardiac death: guilty as charged or falsely accused?. Cleve Clin J Med 2013; 80: 539-544
    CrossrefPubMedSearch in Google Scholar
  • 13 Poluzzi E, Raschi E, Moretti U. et al. Drug-induced torsades de pointes: Data mining of the public version of the FDA Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf 2009; 18: 512-518
    CrossrefPubMedSearch in Google Scholar
  • 14 U.S. Food and Drug Administration (FDA). FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms. Available online: https://www.fda.gov/downloads/Drugs/DrugSafety/UCM343347.pdf (accessed on 30 November 2018)
    PubMed
  • 15 Shaffer D, Singer S, Korvick J. et al. Concomitant risk factors in reports of torsades de pointes associated with macrolide use: Review of the United States Food and Drug Administration adverse event reporting system. Clin Infect Dis 2002; 35: 197-200
    CrossrefPubMedSearch in Google Scholar
  • 16 Ray WA, Murray KT, Meredith S. et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med 2004; 351: 1089-1096
    CrossrefPubMedSearch in Google Scholar
  • 17 U.S. Food and Drug Administration (FDA). FDA Drug Safety Communication: FDA review finds additional data supports the potential for increased long-term risks with antibiotic clarithromycin (Biaxin) in patients with heart disease. Available online: https://www.fda.gov/downloads/Drugs/DrugSafety/UCM597723.pdf (accessed on 30 November 2018).
    PubMed
  • 18 Antzelevitch C, Sun D, Zhang Z. et al. Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. J Am Coll Cardiol 1996; 28: 1836-1848
    CrossrefPubMedSearch in Google Scholar
  • 19 Rubart M, Pressler ML, Pride HP. et al. Electrophysiological mechanisms in a canine model of erythromycin-associated long QT syndrome. Circulation 1993; 88: 1832-1844
    CrossrefPubMedSearch in Google Scholar
  • 20 Duncan RS, Ridley JM, Dempsey CE. et al. Erythromycin block of the hERG Kþ channel: Accessibility to F656 and Y652. Biochem Biophys Res Commun 2006; 341: 500-506
    CrossrefPubMedSearch in Google Scholar
  • 21 Stanat SJ, Carlton CG, Crumb WJ. et al. Characterization of the inhibitory effects of erythromycin and clarithromycin on the HERG potassium channel. Mol Cell Biochem 2003; 254: 1-7
    CrossrefPubMedSearch in Google Scholar
  • 22 Freeman BD, Dixon DJ, Coopersmith CM. et al. Pharmacoepidemiology of QT-interval prolonging drug administration in critically ill patients. Pharmacoepidemiol Drug Saf 2008; 17: 971-981
    CrossrefPubMedSearch in Google Scholar
  • 23 Arellano-Rodrigo E, Garcia A, Mont L. et al. Torsade de pointes and cardiorespiratory arrest induced by azithromycin in a patient with congenital long QT syndrome. Med Clin (Barc) 2001; 117: 118-119
    CrossrefPubMedSearch in Google Scholar
  • 24 Bronstein-Sitton N. The ether-a-go-go Related Gene (ERG) Voltage-Gated K+ Channels: A common structure with uncommon characteristics. Modulator 2006; 21: 13-15
    PubMedSearch in Google Scholar
  • 25 Mauerhöfer M, Bauer CK. Effects of temperature on heteromeric KV11.1a/1b and KV11.3 channels. Biophys J 2016; 111: 504-523
    CrossrefPubMedSearch in Google Scholar
  • 26 Wimmers S, Wulfsen I, Bauer CK. et al. ERG1, ERG2 and ERG3 K channel subunits are able to form heteromultimers. Pflugers Arch 2001; 441: 450-455
    CrossrefPubMedSearch in Google Scholar
  • 27 Curran ME, Splawski I, Timothy KW. et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995; 80: 795-803
    CrossrefPubMedSearch in Google Scholar
  • 28 Sanguinetti MC, Curran ME, Spector PS. et al. Spectrum of HERG K + -channel dysfunction in an inherited cardiac arrhythmia. Proc Natl Acad Sci USA 1996; 93: 2208-2212
    CrossrefPubMedSearch in Google Scholar
  • 29 Zhou Z, Gong Q, January CT. Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome. Pharmacological and temperature effects. J Biol Chem 1999; 274: 31123-31126
    CrossrefPubMedSearch in Google Scholar
  • 30 Neethling A, Long QT syndrome: The Identification and Verification of Putative KCNE2-interacting Proteins. For the degree of Master of Science, Stellenbosch University, Stellenbosch Central, Stellenbosch, 7602, South Africa, December 2013
    PubMed
  • 31 Cheng YJ, Nie XY, Chen XM. et al. The role of macrolide antibiotics in increasing cardiovascular risk. J Am Coll Cardiol 2015; 66: 2173-2184
    CrossrefPubMedSearch in Google Scholar
  • 32 Kim KS, Shin WH, Park SJ. et al. Effect of clebopride, antidopaminergic gastrointestinal prokinetics, on cardiac repolarization. Int J Toxicol 2007; 26: 25-31
    CrossrefPubMedSearch in Google Scholar
  • 33 Luo L, Hu P, Miao C. et al. Clenbuterol attenuates hERG channel by promoting the mature channel degradation. Int J Toxicol 2017; 36: 314-324
    CrossrefPubMedSearch in Google Scholar
  • 34 Volberg WA, Koci BJ, Su W. et al. Blockade of human cardiac potassium channel human ether-a-go-go-related gene (hERG) by macrolide antibiotics. Pharmacol Exp Ther 2002; 302: 320-327
    CrossrefPubMedSearch in Google Scholar
  • 35 Ray WA, Murray KT, Hall K. et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012; 366: 1881-1890
    CrossrefPubMedSearch in Google Scholar
  • 36 Ohtani H, Taninaka C, Hanada E. et al. Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats. Antimicrob Agents Chemother. 2000; 44: 2630-2637
    PubMedSearch in Google Scholar
  • 37 Milberg P, Eckardt L, Bruns HJ. et al. Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: Fast phase 3 repolarization prevents early after depolarizations and torsade de pointes. J Pharmacol Exp Ther 2002; 303: 218-225
    CrossrefPubMedSearch in Google Scholar
  • 38 Abbott GW, Sesti F, Splawski I. et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999; 97: 175-187
    CrossrefPubMedSearch in Google Scholar
  • 39 Han SN, Yang SH, Zhang Y. et al. Blockage of hERG current and the disruption of trafficking as induced by roxithromycin. Can J Physiol Pharmacol 2013; 91: 1112-1118
    CrossrefPubMedSearch in Google Scholar
  • 40 Hancox JC, Du C, El Harchi A. et al. A novel genetic modifier for clarithromycin-related cardiac arrhythmia risk?. Ther Adv Infect Dis 2014; 2: 71-72
    PubMedSearch in Google Scholar
  • 41 Rubart M, Pressler ML, Pride HP. et al. Electrophysiological mechanisms in a canine model of erythromycin-associated long QT syndrome. Circulation 1993; 88: 1832-1844
    CrossrefPubMedSearch in Google Scholar