The Effect of a Synthetic Estrogen, Ethinylestradiol, on the hERG Block by E-4031
Autor: | Keiichi Fukuda, Kazuho Sakamoto, Masahiko Yamaguchi, Mana Sugimoto, Junko Kurokawa, Masaki Ieda, Takeshi Suzuki, Shintaro Sugimoto, Fumiya Tamura |
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Rok vydání: | 2021 |
Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Pyridines hERG Pharmacology Ethinyl Estradiol Microbiology Biochemistry QT interval Article chemistry.chemical_compound synthetic estrogen Estradiol Congeners Piperidines Ethinylestradiol medicine Humans cardiovascular diseases Related gene Molecular Biology cardiac potassium channel drug interaction biology QT intervals Drug interaction Ether-A-Go-Go Potassium Channels QR1-502 Blockade HEK293 Cells chemistry hERG blocker biology.protein E-4031 Ion Channel Gating Synthetic estrogen medicine.drug |
Zdroj: | Biomolecules, Vol 11, Iss 1385, p 1385 (2021) Biomolecules Volume 11 Issue 9 |
ISSN: | 2218-273X |
Popis: | 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. |
Databáze: | OpenAIRE |
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