Download PDF
Planta Med 2016; 82(11/12): 1009-1015
DOI: 10.1055/s-0042-105572
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

hERG Channel Blocking Ipecac Alkaloids Identified by Combined In Silico – In Vitro Screening[*]

Jadel M. Kratz   **
1   Department of Pharmacognosy, University of Vienna, Vienna, Austria
,
Christina E. Mair   **
1   Department of Pharmacognosy, University of Vienna, Vienna, Austria
,
Sarah K. Oettl   **
2   Institute of Pharmacy/Pharmacognosy, University of Innsbruck, Innsbruck, Austria
,
Priyanka Saxena
3   Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
,
Olaf Scheel
4   Cytocentrics Bioscience GmbH, Rostock, Germany
,
Daniela Schuster
5   Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria
,
Steffen Hering
3   Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
,
Judith M. Rollinger
1   Department of Pharmacognosy, University of Vienna, Vienna, Austria
› Author Affiliations
Further Information

Publication History

received 07 March 2016
revised 21 March 2016

accepted 21 March 2016

Publication Date:
04 May 2016 (online)

    Permissions and Reprints

Abstract

Human ether-a-go-go-related gene channel blocking is associated with QT interval prolongation and increased risk of potentially fatal arrhythmias. As natural products keep increasing in popularity, there is an urgent need for studies assessing human ether-a-go-go-related gene channel-related cardiotoxic risks. We selected 49 plant species based on the results of a pharmacophore-based virtual screening campaign, in parallel with a literature data survey concerning highly consumed herbal medicines with reported cardiac liabilities. Lead-like enhanced extracts were prepared, an initial in vitro screening was performed at 100 µg/mL by voltage clamp on Xenopus oocytes, and five human ether-a-go-go-related gene channel blocking extracts were identified. In accordance to the six virtually predicted alkaloids, the root extract of Carapichea ipecacuanha inhibited human ether-a-go-go-related gene channel currents by 32.5 %. A phytochemical workflow resulted in the isolation and identification of five out of the six virtually predicted alkaloids. All isolates blocked human ether-a-go-go-related gene channel currents to different extents. The major ipecac constituents emetine (1) and cephaeline (2) showed IC50 values of 21.4 and 5.3 µM, respectively, measured by whole-cell patch clamp in HEK293 cells. This is the first report on human ether-a-go-go-related gene channel blockers from C. ipecacuanha. Its roots and rhizomes are used to produce different pharmacopeial ipecac preparations that are mainly used as emetics for poisoning treatment. Our findings raise further questions regarding the safety and over-the-counter appropriateness of these herbal products.

Key words

Carapichea ipecacuanha - Rubiaceae - ipecac syrup - ipecac alkaloids - hERG channel - patch clamp

* Dedicated to Professor Dr. Dr. h. c. mult. Kurt Hostettmann.


** These authors contributed equally to this work.


Supporting Information

 

  • References

  • 1 Vandenberg JI, Perry MD, Perrin MJ, Mann SA, Ke Y, Hill AP. hERG K(+) channels: structure, function, and clinical significance. Physiol Rev 2012; 92: 1393-1478
    CrossrefPubMedGoogle Scholar
  • 2 Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature 2006; 440: 463-469
    CrossrefPubMedGoogle Scholar
  • 3 Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003; 89: 1363-1372
    CrossrefPubMedGoogle Scholar
  • 4 Du K, De Mieri M, Saxena P, Phungula KV, Wilhelm A, Hrubaru MM, van Rensburg E, Zietsman PC, Hering S, van der Westhuizen JH, Hamburger M. HPLC-Based activity profiling for Herg channel inhibitors in the South African medicinal plant Galenia africana . Planta Med 2015; 81: 1154-1162
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 De Mieri M, Du K, Neuburger M, Saxena P, Zietsman PC, Hering S, van der Westhuizen JH, Hamburger M. hERG channel inhibitory daphnane diterpenoid orthoesters and polycephalones A and B with unprecedented skeletons from Gnidia polycephala . J Nat Prod 2015; 78: 1697-1707
    CrossrefPubMedGoogle Scholar
  • 6 Schramm A, Baburin I, Hering S, Hamburger M. hERG channel inhibitors in extracts of Coptidis Rhizoma. Planta Med 2011; 77: 692-697
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 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
    CrossrefPubMedGoogle Scholar
  • 8 Alper K, Bai R, Liu N, Fowler SJ, Huang XP, Priori SG, Ruan Y. hERG blockade by Iboga alkaloids. Cardiovasc Toxicol 2016; 16: 14-22
    CrossrefPubMedGoogle Scholar
  • 9 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
    CrossrefPubMedGoogle Scholar
  • 10 Braga RC, Alves VM, Silva MF, Muratov E, Fourches D, Tropsha A, Andrade CH. Tuning hERG out: antitarget QSAR models for drug development. Curr Top Med Chem 2014; 14: 1399-1415
    CrossrefPubMedGoogle Scholar
  • 11 Wang S, Li Y, Xu L, Li D, Hou T. Recent developments in computational prediction of hERG blockage. Curr Top Med Chem 2013; 13: 1317-1326
    CrossrefPubMedGoogle Scholar
  • 12 Beattie KA, Luscombe C, Williams G, Munoz-Muriedas J, Gavaghan DJ, Cui Y, Mirams GR. Evaluation of an in silico cardiac safety assay: using ion channel screening data to predict QT interval changes in the rabbit ventricular wedge. J Pharmacol Toxicol Methods 2013; 68: 88-96
    CrossrefPubMedGoogle Scholar
  • 13 Lee MR. Ipecacuanha: the South American vomiting root. J R Coll Physicians Edinb 2008; 38: 355-360
    PubMedGoogle Scholar
  • 14 De Oliveira LO, Rossi AA, Martins ER, Batista FR, Silva RS. Molecular phylogeography of Carapichea ipecacuanha, an amphitropical shrub that occurs in the understory of both semideciduous and evergreen forests. Mol Ecol 2010; 19: 1410-1422
    CrossrefPubMedGoogle Scholar
  • 15 Garcia RMA, de Oliveira LO, Moreira MA, Barros WS. Variation in emetine and cephaeline contents in roots of wild Ipecac (Psychotria ipecacuanha). Biochem Syst Ecol 2005; 33: 233-243
    CrossrefPubMedGoogle Scholar
  • 16 Keene AT, Phillipson JD, Warhurst DC, Koch M, Seguin E. In vitro amoebicidal testing of natural products; Part 2. Alkaloids related to emetine. Planta Med 1987; 53: 201-206
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Wiegrebe W, Kramer WJ, Shamma M. The emetine alkaloids. J Nat Prod 1984; 47: 397-408
    CrossrefPubMedGoogle Scholar
  • 18 United States Pharmacopeia, 39th edition. Rockville: United States Pharmacopeial Convention; 2016: 3929-3931
    Google Scholar
  • 19 Höjer J, Troutman WG, Hoppu K, Erdman A, Benson BE, Mégarbane B, Thanacoody R, Bedry R, Caravati EM. American Academy of Clinical Toxicology, European Association of Poison Centres and Clinical Toxicologists. Position paper update: ipecac syrup for gastrointestinal decontamination. Clin Toxicol 2013; 51: 134-139
    CrossrefPubMedGoogle Scholar
  • 20 Silber TJ. Ipecac syrup abuse, morbidity, and mortality: isnʼt it time to repeal its over-the-counter status?. J Adolesc Health 2005; 37: 256-260
    CrossrefPubMedGoogle Scholar
  • 21 Berendes J. Des Pedanios Dioskurides aus Anazarbos Arzneimittellehre in fünf Büchern (reprint). Vaduz, Lichtenstein: Sändig Reprints; 1997. (1902)
    Google Scholar
  • 22 König R, Hopp J, Glöckner W, Winkler G. Plinius Secundus d. Ä. Naturkunde, books XX-XVII. Munich, Zurich: Artemis Publisher; 1985
    Google Scholar
  • 23 Pahlow M. Das große Buch der Heilpflanzen. München, Deutschland: Gräfe und Unzer; 1993
    Google Scholar
  • 24 Ausserer O. Volksmedizin in Tirol. EU Interregnum-II-Project. Glurns, Italy: Zentrum zur Dokumentation von Naturheilverfahren; 2001
    Google Scholar
  • 25 Schramm A, Saxena P, Chlebek J, Cahlikova L, Baburin I, Hering S, Hamburger M. Natural products as potential human ether-a-go-go-related gene channel inhibitors – screening of plant-derived alkaloids. Planta Med 2014; 80: 740-746
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 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
    CrossrefPubMedGoogle Scholar
  • 27 Paul AA, Witchel HJ, Hancox JC. Inhibition of the current of heterologously expressed hERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine. Br J Pharmacol 2002; 136: 717-729
    CrossrefPubMedGoogle Scholar
  • 28 Kaufman ES. Quinidine in short QT syndrome: an old drug for a new disease. J Cardiovasc Electrophysiol 2007; 18: 665-666
    CrossrefPubMedGoogle Scholar
  • 29 Medeiros CL, Calixto JB. Effect of the hydroalcoholic extract of Rauwolfia ligustrina on smooth and cardiac muscles in-vitro . J Pharm Pharmacol 1996; 48: 1210-1214
    CrossrefPubMedGoogle Scholar
  • 30 Orvos P, Virág L, Tálosi L, Hajdú Z, Csupor D, Jedlinszki N, Szél T, Varró A, Hohmann J. Effects of Chelidonium majus extracts and major alkaloids on hERG potassium channels and on dog cardiac action potential – a safety approach. Fitoterapia 2015; 100: 156-165
    CrossrefPubMedGoogle Scholar
  • 31 Martin NJ, Ferreiro SF, Barbault F, Nicolas M, Lecellier G, Paetz C, Gaysinski M, Alonso E, Thomas OP, Botana LM, Raharivelomanana P. Indole alkaloids from the Marquesan plant Rauvolfia nukuhivensis and their effects on ion channels. Phytochemistry 2015; 109: 84-95
    CrossrefPubMedGoogle Scholar
  • 32 European Pharmacopeia, 8th edition. Strasbourg: Directorate for the Quality of Medicines & HealthCare of the Council of Europe (EDQM); 2014: 1918-1922
    Google Scholar
  • 33 Wagner C, Bowers W. Cardiomyopathy in a child induced by intentional ipecac poisoning. Air Med J 2006; 25: 236-237
    PubMedGoogle Scholar
  • 34 Rashid N. Medically unexplained myopathy due to ipecac abuse. Psychosomatics 2006; 47: 167-169
    CrossrefPubMedGoogle Scholar
  • 35 Palmer EP, Guay AT. Reversible myopathy secondary to abuse of ipecac in patients with major eating disorders. N Engl J Med 1985; 313: 1457-1459
    CrossrefPubMedGoogle Scholar
  • 36 Ho PC, Dweik R, Cohen MC. Rapidly reversible cardiomyopathy associated with chronic ipecac ingestion. Clin Cardiol 1998; 21: 780-783
    CrossrefPubMedGoogle Scholar
  • 37 Itoh T, Miyazaki M, Fukuoka H, Nagata K, Ohsawa A. Formal total synthesis of (−)-emetine using catalytic asymmetric allylation of cyclic imines as a key step. Org Lett 2006; 8: 1295-1297
    CrossrefPubMedGoogle Scholar
  • 38 Tietze LF, Rackelmann N, Muller I. Enantioselective total syntheses of the Ipecacuanha alkaloid emetine, the Alangium alkaloid tubulosine and a novel benzoquinolizidine alkaloid by using a domino process. Chemistry 2004; 10: 2722-2731
    CrossrefPubMedGoogle Scholar
  • 39 Ma WW, Anderson JE, McKenzie AT, Byrn SR, McLaughlin JL, Hudson MS. Tubulosine: an antitumor constituent of Pogonopus speciosus . J Nat Prod 1990; 53: 1009-1014
    CrossrefPubMedGoogle Scholar
  • 40 Fujii T, Yamada K, Minami S, Yoshifuji S, Ohba M. Quinolizidines. VIII. Structure and synthesis of the Alangium alkaloid alangicine: Syntheses of (±)- and (+)-Alangicines. Chem Pharm Bull (Tokyo) 1983; 31: 9
    PubMedGoogle Scholar
  • 41 Manno BR, Manno JE. Toxicology of ipecac: a review. Clin Toxicol 1977; 10: 221-242
    CrossrefPubMedGoogle Scholar
  • 42 Scharman EJ, Hutzler JM, Rosencrance JG, Tracy TS. Single dose pharmacokinetics of syrup of ipecac. Ther Drug Monit 2000; 22: 566-573
    CrossrefPubMedGoogle Scholar
  • 43 Moran DM, Crouch DJ, Finkle BS. Absorption of ipecac alkaloids in emergency patients. Ann Emerg Med 1984; 13: 1100-1102
    CrossrefPubMedGoogle Scholar
  • 44 Lachman MF, Romeo R, McComb RB. Emetine identified in urine by HPLC, with fluorescence and ultraviolet/diode array detection, in a patient with cardiomyopathy. Clin Chem 1989; 35: 499-502
    PubMedGoogle Scholar
  • 45 Yamashita M, Yamashita M, Azuma J. Urinary excretion of ipecac alkaloids in human volunteers. Vet Hum Toxicol 2002; 44: 257-259
    PubMedGoogle Scholar
  • 46 Sutphen JL, Saulsbury FT. Intentional ipecac poisoning: Munchausen syndrome by proxy. Pediatrics 1988; 82: 453-456
    PubMedGoogle Scholar
  • 47 Rollinger JM, Haupt S, Stuppner H, Langer T. Combining ethnopharmacology and virtual screening for lead structure discovery: COX-inhibitors as application example. J Chem Inf Comput Sci 2004; 44: 480-488
    CrossrefPubMedGoogle Scholar
  • 48 Stork D, Timin EN, Berjukow S, Huber C, Hohaus A, Auer M, Hering S. State dependent dissociation of hERG channel inhibitors. Br J Pharmacol 2007; 151: 1368-1376
    PubMedGoogle Scholar
  • 49 Baburin I, Beyl S, Hering S. Automated fast perfusion of Xenopus oocytes for drug screening. Pflugers Archiv 2006; 453: 117-123
    PubMedGoogle Scholar
  • 50 Scheel O, Himmel H, Rascher-Eggstein G, Knott T. Introduction of a modular automated voltage-clamp platform and its correlation with manual human Ether-a-go-go related gene voltage-clamp data. Assay Drug Dev Technol 2011; 9: 600-607
    CrossrefPubMedGoogle Scholar