hERG Channel Inhibitors in Extracts of Coptidis Rhizoma

Abstract

Inhibition of the hERG channel delays repolarization and prolongs the QT interval and cardiac action potential which can lead to sudden death. Several drugs have been withdrawn from the market due to hERG channel inhibition. In the search of hERG channel inhibitors of natural origin, we established an HPLC-based profiling approach which combines HPLC-microfractionation and bioactivity testing on Xenopus laevis oocytes. The methanolic extract of the TCM herbal drug Coptidis rhizoma (Coptis chinensis Franch., Ranunculaceae) reduced the peak tail hERG current by 31.7 ± 2.0% at 100 µg/mL. HPLC-based activity profiling pointed towards berberine as the active constituent. However, hERG inhibition by 100 µM of a reference sample of berberine (16.3 ± 1.6%) was less pronounced than previously reported. Subsequent LC-PDA-MS analysis showed that berberine collected by microfractionation of the Coptis extract had been, in part, transformed to active dihydroberberine. Formic acid added to the HPLC mobile phase to reduce peak tailing of protoberberine alkaloids acted as a reducing reagent according to the mechanism of the Leuckart-Wallach reaction. Among other structurally related protoberberines tested, dihydroberberine (30.1 ± 10.1% at 100 µM) was the most potent hERG inhibitor.

hERG Channel Inhibitory Daphnane Diterpenoid Orthoesters and Polycephalones A and B with Unprecedented Skeletons from Gnidia polycephala

“…7 For a broader risk assessment, we recently screened a selection of widely used food and medicinal plants 10 and identified the major alkaloid dihydroberberine in the traditional Chinese herbal drug Huanglian (rhizome of Coptis chinensis Franch., Ranunculaceae) as a compound with mild hERG-inhibitory properties in the Xenopus oocyte assay. 11 As a follow-up, we screened a diverse collection of alkaloids found in medicinal plants and identified additional alkaloids with in vitro hERGblocking properties. 8 We extended the assessment of possible hERG liabilities by screening an extract library generated from 142 medicinal plants used in southern Africa.…”

Effects of Chelidonium majus extracts and major alkaloids on hERG potassium channels and on dog cardiac action potential — A safety approach

“…However, several studies have demonstrated that berberine [6][7][8][9], chelerythrine [10], chelidonine [11], sanguinarine [11], and protopine [11] have hERG ion channel activities. The human ether-à-go-go-related gene (hERG, KCNH2, Kv11.1) encodes a cardiac voltage-gated potassium channel that provides the major repolarizing current (rapidly activating delayed rectifier potassium current, I Kr ) in phase 3 of the cardiac action potential.…”

“…Among these alkaloids, berberine was reported to inhibit hERG potassium current in transfected HEK cells expressing hERG channels [7][8][9], to block delayed rectifier potassium (I Kr ) current in cardiac myocytes [6], and to increase action potential duration on cardiac preparations [6,7]. Chelerythrine was also described to inhibit hERG current [10] and prolong action potential [12].…”

The enhancement of cardiac toxicity by concomitant administration of Berberine and macrolides

“…In recent years, some researches proved that use of BBR combined with antibacterial agents (azithromycin, cefazoline and levofloxacin) was against clinical Multi-Drug resistant isolates of Methicillin-Resistant Staphylococcus aureus (MRSA) (Zuo et al, 2012). Several studies indicated that BBR and CLR inhibited hERG currents (Nilsson and Webster, 2014;Schramm et al, 2011). All macrolide antibiotics except AZM are metabolized by the liver.…”