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Archives of Pharmacal Research

, Volume 39, Issue 12, pp 1644–1652 | Cite as

P21 (Cdc42/Rac)-activated kinase 1 (pak1) is associated with cardiotoxicity induced by antihistamines

  • Jaesuk YunEmail author
  • So Young Kim
  • Kyung Sik Yoon
  • Heejung Shin
  • Ho-Sang Jeong
  • Hyejoo Chung
  • Young-Hoon Kim
  • Jisoon Shin
  • Hye Jin Cha
  • Kyoung moon Han
  • Seungha Hyeon
  • Tac-hyung Lee
  • Hye-Kyung Park
  • Hyung Soo KimEmail author
Research Article

Abstract

Astemizole, a non-sedating histamine H1 receptor blocker, is widely known to cause cardiac arrhythmia, which prolongs the QT interval. However, the precise molecular mechanism involved in antihistamine-induced cardiovascular adverse effects other than hERG channel inhibition is still unclear. In this study, we used DNA microarray analysis to detect the mechanisms involved in life-threatening adverse effects caused by astemizole. Rat primary cardiomyocytes were treated with various concentrations of astemizole for 24 h and the corresponding cell lysates were analyzed using a DNA microarray. Astemizole altered the expression profiles of genes involved in calcium transport/signaling. Using qRT-PCR analysis, we demonstrated that, among those genes, p21 (Cdc42/Rac)-activated kinase 1 (pak1) mRNA was downregulated by treatment with terfenadine and astemizole. Astemizole also reduced pak1 protein levels in rat cardiomyocytes. In addition, astemizole decreased pak1 mRNA and protein levels in H9c2 cells and induced an increase in cell surface area (hypertrophy) and cytotoxicity. Fingolimod hydrochloride (FTY720), a pak1 activator, inhibited astemizole-induced hypertrophy and cytotoxicity in H9c2 cells. These results suggest that antihistamine-induced cardiac adverse effects are associated with pak1 expression and function.

Keywords

Antihistamine Astemizole Genomics Cardiotoxicity 

Notes

Acknowledgments

This research was supported by a grant (15181MFDS482, 08171MFDS503, 07151MFDS671) from the Ministry of Food and Drug Safety.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

12272_2016_840_MOESM1_ESM.tif (2.4 mb)
Supplementary material 1 (TIF 2420 kb)
12272_2016_840_MOESM2_ESM.tif (186 kb)
Supplementary material 2 (TIF 186 kb)

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Copyright information

© The Pharmaceutical Society of Korea 2016

Authors and Affiliations

  • Jaesuk Yun
    • 1
    Email author
  • So Young Kim
    • 1
  • Kyung Sik Yoon
    • 1
  • Heejung Shin
    • 1
  • Ho-Sang Jeong
    • 1
  • Hyejoo Chung
    • 1
  • Young-Hoon Kim
    • 1
  • Jisoon Shin
    • 1
  • Hye Jin Cha
    • 1
  • Kyoung moon Han
    • 1
  • Seungha Hyeon
    • 1
  • Tac-hyung Lee
    • 1
  • Hye-Kyung Park
    • 1
  • Hyung Soo Kim
    • 1
    Email author
  1. 1.Pharmacological Research DivisionNational Institute of Drug and Safety Evaluation, Ministry of Food and Drug SafetyCheongjuRepublic of Korea

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