Pick your poison: hERG-blocking alkaloids in the emetic herbal drug ipecac

The human ether a-go-go related gene (hERG) channel is an important antitarget associated with QT interval prolongation and increased risk of fatal arrhythmias [1]. Although hERG-safety evaluation is mandatory in formal drug discovery, natural products are rarely evaluated. As botanicals continue to rise in popularity, there is an urgent need for hERG-related cardiotoxic risks assessment. Here, we implemented in silico/in vitro approaches for the fast identification of hERG-blocking constituents in highly consumed herbal remedies. Firstly, we virtually screened a multi-conformational 3D molecular natural product database with a previously validated pharmacophore model [2]. For pharmacological profiling, lead-like enhanced extracts from virtually predicted and commonly consumed botanicals (n = 55) were prepared [3] and screened in Xenopus oocytes (100 µg/mL). The combined approach revealed 32.5% hERG blockade for the Carapichea ipecacuanha root extract, and six virtually predicted blockers from the group of ipecac alkaloids. Chromatographic separation resulted in the isolation and identification of five alkaloids (emetine, cephaeline, N-methylemetine, psychotrine and O-methylpsychotrine). All compounds were virtual hits and blocked hERG currents to different extents in vitro. The underground parts of C. ipecacuanha, alkaloid-enriched organs, are extracted for producing ipecac syrup, which is used as an emetic in emergency poisoning. Major ipecac constituents, emetine and cephaeline, showed IC₅₀ values of 21.4 and 5.3µM, respectively, in HEK293 cells. Chronic abuse of ipecac products is known to induce cardiotoxicity in patients with eating disorders. However, this is the first report on the hERG-blockage of ipecac's major alkaloids. Our findings raise further questions regarding the safety of such herbal products, especially due to their tissue accumulation [4]. If combined with drugs or dietary supplements containing hERG blockers [5] they might boost cardiotoxicity.

Acknowledgements: This work was supported by a Marie Curie International Research Staff Exchange Scheme (IRSES) Fellowship within the Seventh European Community Framework Programme (hERGscreen, 295174) and by the Austrian Science Fund (FWF P24587). D.S. is supported by the Erika Cremer Habilitation Program of the University of Innsbruck. We thank Catharina Willi for her valuable contribution in the phytochemical work.

Keywords: Carapichea ipecacuanha, Rubiaceae, ipecac syrup, alkaloids, hERG, patch clamp.

References:

[1] Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature 2006; 440: 463 – 469

[2] Kratz JM, Schuster D, Edtbauer M, Saxena P, Mair CE, Kirchebner J, Matuszczak B, Baburin I, Hering S, Rollinger JM. Experimentally validated HERG pharmacophore models as cardiotoxicity prediction tools. J Chem Inf Model 2014; 54: 2887 – 2901

[3] Camp D, Davis RA, Campitelli M, Ebdon J, Quinn RJ. Drug-like properties: guiding principles for the design of natural product libraries. J Nat Prod 2012; 75: 72 – 81

[4] Scharman EJ, Hutzler JM, Rosencrance JG, Tracy TS. Single dose pharmacokinetics of syrup of ipecac. Ther Drug Monit 2000; 22: 566 – 573

[5] Grienke U, Mair CE, Saxena P, Baburin I, Scheel O, Ganzera M, Schuster D, Hering S, Rollinger JM. Human Ether-a-go-go Related Gene (hERG) Channel Blocking Aporphine Alkaloids from Lotus Leaves and Their Quantitative Analysis in Dietary Weight Loss Supplements. J Agric Food Chem 2015; 63: 5634 – 5639

No conflict of interest has been declared by the author(s).