The effect of a synthetic estrogen, ethinylestradiol, on the herg block by e-4031

Fumiya Tamura, Shintaro Sugimoto, Mana Sugimoto, Kazuho Sakamoto, Masahiko Yamaguchi, Takeshi Suzuki, Keiichi Fukuda, Masaki Ieda, Junko Kurokawa

Research output: Contribution to journalArticlepeer-review

Abstract

Inhibition of K+-conductance through the human ether-a-go-go related gene (hERG) channel leads to QT prolongation and is associated with cardiac arrhythmias. We previously reported that physiological concentrations of some estrogens partially suppress the hERG channel currents by interacting with the S6 residue F656 and increase the sensitivity of hERG blockade by E-4031. Although these studies suggested that clinically used synthetic estrogens with similar structures have the marked potential to alter hERG functions, the hERG interactions with synthetic estrogens have not been assessed. We therefore examined whether ethinylestradiol (EE2), a synthetic estrogen used in oral contraceptives, affects hERG function and blockade by drugs. Supratherapeutic concentrations of EE2 did not alter amplitudes or kinetics of the hERG currents elicited by train pulses at 20 mV (0.1 Hz). On the other hand, EE2 at therapeutic concentrations reduced the degree of hERG current suppression by E-4031. The administration of EE2 followed by E-4031 blockade reversed the current suppression, suggesting that the interaction of EE2 and E-4031 alters hERG at the drug-binding site. The effects of EE2 on hERG blockade raised the possibility that other estrogens, including synthetic estrogens, can alter hERG blockade by drugs that cause QT prolongation and ventricular arrhythmias.

Original languageEnglish
Article number1385
JournalBiomolecules
Volume11
Issue number9
DOIs
Publication statusPublished - 2021 Sep

Keywords

  • Cardiac potassium channel
  • Drug interaction
  • HERG blocker
  • QT intervals
  • Synthetic estrogen

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Fingerprint

Dive into the research topics of 'The effect of a synthetic estrogen, ethinylestradiol, on the herg block by e-4031'. Together they form a unique fingerprint.

Cite this