Inhibitory effect of terfenadine on Kir2.1 and Kir2.3 channels

• Published in: Acta pharmaceutica (Zagreb, Croatia) Vol. 71; no. 2; pp. 317 - 324
• Main Authors: Delgado-Ramírez, Mayra, Rodriguez-Leal, Fanny Junue, Rodríguez-Menchaca, Aldo Azmar, Moreno-Galindo, Eloy Gerardo, Sanchez-Chapula, José Antonio, Ferrer, Tania
• Format: Journal Article
• Language: English
• Published: Poland Sciendo 01.06.2021; De Gruyter Poland
• Subjects: Anticancer properties; Antihistamines; Antitumor activity; cationic amphiphilic drugs; Channels; HEK293 Cells; Histamine H1 Antagonists, Non-Sedating - administration & dosage; Histamine H1 Antagonists, Non-Sedating - pharmacology; Humans; Inhibitory Concentration 50; inward rectifier potassium channels; phosphatidylinositol 4,5-bisphosphate; Phosphatidylinositol 4,5-diphosphate; Potassium; Potassium channels; Potassium channels (inwardly-rectifying); Potassium Channels, Inwardly Rectifying - drug effects; Potassium Channels, Inwardly Rectifying - metabolism; Side effects; Terfenadine; Terfenadine - administration & dosage; Terfenadine - pharmacology; terfenadine; inward rectifier potassium channels; cationic amphiphilic drugs; phosphatidylinositol 4,5-bisphosphate
• ISSN: 1846-9558; 1330-0075; 1846-9558
• DOI: 10.2478/acph-2021-0017

Terfenadine is a second-generation H1-antihistamine that despite potentially can produce severe side effects it has recently gained attention due to its anticancer properties. Lately, the subfamily 2 of inward rectifier potassium channels (Kir2) has been implicated in the progression of some tumoral processes. Hence, we characterized the effects of terfenadine on Kir2.x channels expressed in HEK-293 cells. Terfenadine inhibited Kir2.3 channels with a strikingly greater potency ( = 1.06 ± 0.11 μmol L ) compared to Kir2.1 channels ( = 27.8 ± 4.8 μmol L ). The Kir2.3(I213L) mutant, possessing a larger affinity for phosphatidylinositol 4,5-bisphosphate (PIP ) than the wild-type Kir2.3, was less sensitive to terfenadine inhibition ( = 13.0 ± 2.9 μmol L ). Additionally, the PIP intracellular application had largely reduced the inhibition of Kir2.1 channels by terfenadine. Our data support that Kir2.x channels are targets of terfena-dine by affecting their interaction with PIP , which could be regarded as a mechanism of the antitumor properties of terfenadine.