Flavonoids and hERG channels: Friends or foes?

Simona Saponara; Fabio Fusi; Daniele Iovinelli; Amer Ahmed; Alfonso Trezza; Ottavia Spiga; Giampietro Sgaragli; Massimo Valoti

doi:10.1016/j.ejphar.2021.174030

Flavonoids and hERG channels: Friends or foes?

Eur J Pharmacol. 2021 May 15:899:174030. doi: 10.1016/j.ejphar.2021.174030. Epub 2021 Mar 13.

Authors

Simona Saponara¹, Fabio Fusi², Daniele Iovinelli³, Amer Ahmed¹, Alfonso Trezza³, Ottavia Spiga³, Giampietro Sgaragli⁴, Massimo Valoti¹

Affiliations

¹ Dipartimento di Scienze della Vita, Università degli Studi di Siena, via A. Moro 2, 53100, Siena, Italy.
² Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro 2, 53100, Siena, Italy. Electronic address: fabio.fusi@unisi.it.
³ Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro 2, 53100, Siena, Italy.
⁴ Dipartimento di Scienze della Vita, Università degli Studi di Siena, via A. Moro 2, 53100, Siena, Italy; Accademia Italiana della Vite e del Vino, via Logge degli Uffizi Corti 1, 50122, Florence, Italy.

PMID: 33727059
DOI: 10.1016/j.ejphar.2021.174030

Abstract

The cardiac action potential is regulated by several ion channels. Drugs capable to block these channels, in particular the human ether-à-go-go-related gene (hERG) channel, also known as K_V11.1 channel, may lead to a potentially lethal ventricular tachyarrhythmia called "Torsades de Pointes". Thus, evaluation of the hERG channel off-target activity of novel chemical entities is nowadays required to safeguard patients as well as to avoid attrition in drug development. Flavonoids, a large class of natural compounds abundantly present in food, beverages, herbal medicines, and dietary food supplements, generally escape this assessment, though consumed in consistent amounts. Continuously growing evidence indicates that these compounds may interact with the hERG channel and block it. The present review, by examining numerous studies, summarizes the state-of-the-art in this field, describing the most significant examples of direct and indirect inhibition of the hERG channel current operated by flavonoids. A description of the molecular interactions between a few of these natural molecules and the Rattus norvegicus channel protein, achieved by an in silico approach, is also presented.

Keywords: (±)-Naringenin (PubChem CID: 932); (±)-Taxifolin (PubChem CID: 439533); 7,8-Dimethoxyflavone (PubChem CID:689014); Acacetin (PubChem CID: 5280442); Apigenin (PubChem CID: 5280443); Apigenin trimethyl-ether (PubChem CID: 79730); Baicalein (PubChem CID: 5281605); Daidzein (PubChem CID: 5281708); Docking simulation; Epigallocatechin gallate (PubChem CID: 65064); Fisetin (PubChem CID: 5281614); Flavonoid; Galangin (PubChem CID: 5281616); Genistein (PubChem CID: 5280961); Hesperetin (PubChem CID: 72281); Isorhamnetin (PubChem CID: 5281654); Kaempferol (PubChem CID: 5280863); Liquiritigenin (PubChem CID: 114829); Long QT syndrome; Luteolin (PubChem CID: 5280445); Morin (PubChem CID 5281670); Myricetin (PubChem CID: 5281672); Naringin (PubChem CID: 442428); Patch-clamp; Quercetin (PubChem CID: 5280343); Rutin (PubChem CID: 5280805); Silybinin (PubChem CID: 31553); Torsades de pointes; hERG channel.

Publication types

Review

MeSH terms

Action Potentials
Animals
ERG1 Potassium Channel / antagonists & inhibitors*
ERG1 Potassium Channel / chemistry
ERG1 Potassium Channel / metabolism
Flavonoids / toxicity*
Heart Rate / drug effects*
Humans
Long QT Syndrome / chemically induced*
Long QT Syndrome / metabolism
Long QT Syndrome / physiopathology
Myocytes, Cardiac / drug effects*
Myocytes, Cardiac / metabolism
Potassium Channel Blockers / toxicity*
Protein Conformation
Risk Assessment
Risk Factors
Structure-Activity Relationship
Torsades de Pointes / chemically induced*
Torsades de Pointes / metabolism
Torsades de Pointes / physiopathology

Substances

ERG1 Potassium Channel
Flavonoids
KCNH2 protein, human
Potassium Channel Blockers