hERG Channel-Related Cardiotoxicity Assessment of 13 Herbal Medicines

Hyekyung Ha; Sion Lee; Dong-Hyun Kim; Chang-Seob Seo; Hyeun-kyoo Shin; Ha, Hyekyung; Lee, Sion; Kim, Dong-Hyun; Seo, Chang-Seob; Shin, Hyeun-kyoo

doi:10.13048/jkm.21024

JKM > Volume 42(3); 2021 > Article

Ha, Lee, Kim, Seo, and Shin: hERG Channel-Related Cardiotoxicity Assessment of 13 Herbal Medicines

Original Article

The Journal of Korean Medicine 2021; 42(3): 44-55.

Published online: September 01, 2021

DOI: https://doi.org/10.13048/jkm.21024

hERG Channel-Related Cardiotoxicity Assessment of 13 Herbal Medicines

Hyekyung Ha¹

, Sion Lee²

, Dong-Hyun Kim²

, Chang-Seob Seo¹

, Hyeun-kyoo Shin¹^{, *}

¹KM Science Research Division, Korea Institute of Oriental Medicine

²New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation

Correspondence to: Hyeun-Kyoo Shin, KMD, Ph.D., Herbal Medicine Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Daejeon 34054, Republic of Korea., Tel: +82-42-868-9464, Fax: +82-42-864-2120, E-mail: hkshin@kiom.re.kr

Received May 3, 2021 Revised July 8, 2021 Accepted July 28, 2021

Abstract

Objectives

As the use of herbal medicinal products (HMPs) increases worldwide, systematic verification of the safety of HMPs is required. The induction of cardiotoxicity is one of the major factors in post-approval withdrawal of medicinal products, and drug-induced cardiotoxicity assessment is emerging as an important step in drug development. In the present study, we evaluated human ether-à-go-go-related gene (hERG) potassium channel-related cardiotoxicity to predict the risk of cardiac arrhythmia in thirteen herbal medicines known to have cardiac toxicity.

Methods

We measured the inhibition rate of hERG potassium channel activity of 13 medicinal herbal extracts in hERG-expressing HEK 293 cells using an automated patch-clamping system. Quinidine was used as a positive control for inhibition of hERG activity.

Results

Extracts of Evodiae Fructus, Strychni Semen, and Corydalis Tuber potently inhibited the activity of hERG, and IC₅₀ values were 3.158, 19.87, and 41.26 μg/mL, respectively. Cnidi Fructus, Ephedra Herba, Lithospermi Radix, Polygoni Multiflori Radix, Visci Ramulus et Folium, Asiasari Radix et Rhizoma, and Scolopendra weakly inhibited hERG activity, and the IC₅₀ value for each herbal medicine was more than 400 μg/mL. Aconiti Kusnezoffii Tuber and two types of Aconiti Lateralis Radix Preparata (Po and Yeom) had weak inhibitory activity against hERG, and the IC₅₀ values were more than 700 μg/mL. The IC₅₀ value of quinidine against hERG was 1.021 μM.

Conclusion

Evodiae Fructus, Strychni Semen, and Corydalis Tuber acted as potent inhibitors against hERG. These herbal medicines may cause cardiac arrhythmia through QT prolongation, so care should be taken when taking them.

Keywords: Herbal medicine, Cardiotoxicity, Cardiac arrhythmia, hERG potassium channel

% hERG activity = \frac{peak hERG tail current post - sample treatment}{peak hERG tail current pre - sample treatment} \times 100

Fig. 1

hERG potassium channel activity and concentration-response curves of hERG activity by quinidine (hERG inhibitor) and 13 herbal medicines in hERG-HEK 293 cells. (A) Sample voltage-dependent current traces by hERG channel activities pre/post-treatment of quinidine (10 ìM). (B) Concentration dependent inhibition of hERG channel activities by quinidine. (C-O) Concentration dependent inhibition rate of hERG channel activities by 13 herbal medicine extracts. Data are presented as normalized %hERG activities and means ± standard error (n ≥ 4).

Table 1

The extraction yield of herbal medicines

Herbal name		Scientific name	Family	Origin	Yield of extract (%)
Aconiti Kusnezoffii Tuber	초오	Aconitum kusnezoffii Reichb.	Ranunculaceae	Gyeongju, Korea	15.0
Aconiti Lateralis Radix Preparata (Po type)	부자 (포)	Aconitum carmichaeli Debeaux	Ranunculaceae	China	16.7
Aconiti Lateralis Radix Preparata (Yeom type)	부자 (염)	Aconitum carmichaeli Debeaux	Ranunculaceae	China	41.1
Asiasari Radix et Rhizoma	세신	Asiasarum sieboldii Miquel var. seoulense Nakai	Aristolochiaceae	China	20.2
Cnidi Fructus	사상자	Torilis japonica Decandolle	Umbelliferae	Mungyeong, Korea	10.9
Corydalis Tuber	현호색	Corydalis ternata Nakai	Fumariaceae	Sancheong, Korea	12.9
Ephedrae Herba	마황	Ephedra sinica Stapf	Ephedraceae	China	16.1
Evodiae Fructus	오수유	Evodia rutaecarpa Bentham	Rutaceae	China	21.9
Lithospermi Radix	자근	Lithospermum erythrorhizon Siebold et Zuccarini	Borraginaceae	Danyang, Korea	21.8
Polygoni Multiflori Radix	하수오	Polygonum multiflorum Thunberg	Polygonaceae	China	4.7
Scolopendra	오공	Scolopendra subspinipes mutilans Linné Koch	Scolopendridae	Indonesia	22.5
Strychni Semen	마전자	Strychnos nux-vomica Linné	Loganiaceae	China	5.1
Visci Ramulus et Folium	곡기생	Viscum album L. var. coloratum Ohwi	Loranthaceae	Samcheok, Korea	19.1

Table 2

The IC₅₀ values of quinidine and herbal extracts on hERG potassium channel activity in HEK 293 cells.

Name	Abbreviation		IC₅₀ (μg/mL)

Quinidine (positive control)			1.021 μM
Aconiti Kusnezoffii Tuber	AKT	초오	> 1000
Aconiti Lateralis Radix Preparata (Po type)	ALRP_Po	부자 (포)	> 1000
Aconiti Lateralis Radix Preparata (Yeom type)	ALRP_Yeom	부자 (염)	735.5
Asiasari Radix et Rhizoma	ARR	세신	> 1000
Cnidi Fructus	CF	사상자	469.0
Corydalis Tuber	CT	현호색	41.26
Ephedrae Herba	EH	마황	509.5
Evodiae Fructus	EF	오수유	3.158
Lithospermi Radix	LR	자근	996.5
Polygoni Multiflori Radix	PMR	하수오	650.8
Scolopendra	SP	오공	> 1000
Strychni Semen	SS	마전자	19.87
Visci Ramulus et Folium	VRF	곡기생	760.7

참고문헌

1. College of oriental medicine. Korean medicine dictionary. Seoul: Oriental medical research institute publisher;1985. p. 139

2. Shin HD, Jeong JU. 2011; Study of toxicity presence classification about herbal diet in Tang-aec-pyeon of Dong-ui-bo-gam. Journal of Korean Medicine. 32:1. 12–35.

3. Cho JH, Yoon HI. Essentials of toxicology. Seoul: MIP Publishing Group;2006. p. 349–66.

4. Choi SN, Kwon OB, Lee SO, Seo CS, Shin HK. 2019. Cardiac safety assessment of medicinal herbal formulas using hERG-HEK 293 cell. Journal of Korean Medicine. 40:2. 94–105. https://doi.org/10.13048/jkm.19020

5. Han DH, Kwon KB, Hwang IJ, Kim WK, Kim HC, Oh KS, et al. 2001; Effects of Sylso-san water extract on beating rate in cultured myocardial cells damaged by XO/HX. Korean Journal of Oriental Medical Physiology & Pathology. 15:4. 566–570.

6. You BS, Jung JE, Park JY, Yun JM, Lee I, Moon BS. 2004; Protective effects of Dohongsamul-tang on Zinc-mediated cytotoxicity in H9c2 cardiomyoblast cells. Korean Journal of Oriental Medical Physiology & Pathology. 18:5. 1374–1381.

7. Shin MK, Hwang HJ, Kim SC, Byun JS. 2002; Effect of Banhasasim-tang on the cardiac toxicity and clinical symptom induced by doxorubicin. Korean Journal of Oriental Medical Prescription. 10:1. 131–142.

8. Su CP, Wang Q, Zhang HM, Ren YL, Wang W, Guo SZ. 2020. Literatures analysis on protective role of Chinese herbs on cardiotoxicity induced by chemotherapy drugs. Chinese Journal of Integrated Traditional and Western Medicine. 40:7. 796–800. https://doi.org/10.7661/j.cjim.20200422.229

9. Vicente J, Strauss DG, Upreti VV, Fossler MJ, Sager PT, Noveck R. 2019. The potential role of the J-Tpeak interval in proarrhythmic cardiac safety: Current state of the science from the American College of Clinical Pharmacology and the Cardiac Safety Research Consortium. Journal of Clinical Pharmacology. 59:7. 909–914. https://doi.org/10.1002/jcph.1411

10. National Institute of Food and Drug Safety Evaluation. Guidelines for cardiovascular pharmacology testing. Osong. 2020; 1–26.

11. Paul AA, Witchel HJ, Hancox JC. 2002. Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine. British Journal of Pharmacology. 136:5. 717–729. https://doi.org/10.1038/sj.bjp.0704784

12. Yu R, Li B, Wang YX, Zhu MJ. 2019; Consideration on cardiotoxicity and clinical safety evaluation method of Chinese materia medica. Chinese Traditional and Herbal Drugs. 50:18. 4485–4489. https://doi.org/10.7501/j.issn.0253-2670.2019.18.031

13. Sanguinetti MC, Tristani-Firouzi M. 2006. hERG potassium channels and cardiac arrhythmia. Nature. 440:7083. 463–469. https://doi.org/10.1038/nature04710

14. Wang T, Chen XN, Yu JH, Du QQ, Zhu J, Yang MZ, et al. 2018. High-throughput electrophysiology screen revealed cardiotoxicity of strychnine by selectively targeting hERG channel. American Journal of Chinese Medicine. 46:8. 1825–1840. https://doi.org/10.1142/S0192415X1850091X

15. Zhang YH, Yan CC, Wang F, Li BX, Yang BF. 2019. Advances in research on the mechanism of long-QT syndrome caused by traditional Chinese medicine affecting hERG potassium channel. Acta Pharmaceutica Sinica. 54:11. 1881–1887. https://doi.org/10.16438/j.0513-4870.2019-0369

16. Pan XG, Yan BH, Zhou J, Cao XY, Peng C. 2020. Research progress of Chinese Materia Medica-induced cardiotoxicity. Progress in Pharmaceutical Sciences. 44:10. p. 730–742.

17. Igor B, Rosanne V, Anja S, Priyanka S, Stanislav B, Phillip S, et al. 2018. Dehydroevodiamine and hortiamine, alkaloids from the traditional Chinese herbal drug Evodia rutaecarpa, are IKr blockers with proarrhythmic effects in vitro and in vivo . Pharmacological Research. 131:150–163. https://doi.org/10.1016/j.phrs.2018.02.024

18. Li MH, Zhang GG, Zhao DH. 1997. Effects of brucine on slow action potentials in guinea pig papillary muscle. Pharmacology and Clinics of Chinese Materia Medica. 13:4. 19–21. https://doi.org/10.13412/j.cnki.zyyl.1997.04.009

19. Meng HX, Yao MJ, Ren JU, Liu JX. 2018. Effects of tertiary alkaloids and quaternary alkaloids of Rhizoma Corydalis on action potential in guinea pig ventricular myocytes and hERG channel currents. World Chinese Medicine. 13:1. 1–4. https://doi.org/10.3969/j.issn.1673-7202.2018.01.001

20. Zhang XD, Yu YM, Fan CL, Zhang YZ. 2009; The protective effects of osthol against adriamycin-induced cardiotoxicity in rats. Modern Pharmacy and Clinic. 24:6. 358–359.

21. Li L, Zhuang FE, Yang L, Zhang CL, Zhao GS, Zhao DK. 1995; Effects of osthole on isolated guinea pig heart atria. Acta Pharmacologica Sinica. 16:3. 251–254.

22. Li L, Zhuang FE, Zhang CL, Zhao GS, Zhao DK. 1995; Effects of osthole on slow action potentials and right atria frequency. Chinese Journal of Pharmacology and Toxicology. 9:2. 108–122.

23. Kwak YG, Kim DK, Ma TZ, Park SA, Park H, Jung YH, et al. 2006. Torilin from Torilis japonica (Houtt.) DC. blocks hKv1.5 channel current. Archives of Pharmacal Research. 29:10. 834–839. https://doi.org/10.1007/BF02973902

24. He YM, Zhong QQ, Wang K, Wang MR, Yang H, Lin JC. 2010; Cardiotoxicity of Ephedra to rabbit model system. Journal of Huazhong Agricultural University. 29:4. 484–488.

25. Hong LZ, Li JL, Chen YJ, Jin GY. 2007; Effect of Ephedra vulgans Fruit polysaccharide (EVFP) on electric potential of ventricular papillary muscle in rabbits. Lishizhen Medicine and Materia Medica Research. 18:6. 1367–1368.

26. Gui C, Chen MH, Lin S, Wei YX. 2010; Cytotoxicity effects of shikonin on rat cardiomyocytes in vitro. Pharmacology and Clinics of Chinese Materia Medica. 26:6. 33–36.

27. Liu M, Yang CI, Meng QX. 2020. Shikonin attenuates hypoxia-reoxygenation-induced injury of cardiomyocyte cell line H9c2. Basic & Clinical Medicine. 40:3. 380–387. http://journal11.magtechjournal.com/Jwk_jcyxylc/EN/Y2020/V40/I3/380

28. Kim WS, Lim SS, Kang HS, Choue CW, Kim KS, Song JS, et al. 2000; Cardiovascular aspects of aconitine poisoning. Korean Circulation Journal. 30:7. 855–860.

29. Zhang L, Liu CA, Li WH, Liu FL, Zhai XY, Jin C, et al. 2014; Toxic effect and mechanism on rat’s myocardial cell of Radix Aconiti Kusnezoffii and the compatibility of Radix Aconiti Kusnezoffii with Fructus Trichosanthis and Bletillae Rhizoma. Journal of Jiangxi University of Traditional Chinese Medicine. 26:2. 60–63.

30. Wen YY, Wang LP, Shen ZB, Zhuang SQ, Jiang T, Tang CP. 2019. Effects and mechanism of Aconitum vilmorinianum and its processed product on cardiotoxicity. Journal of Chinese Medicinal Materials. 42:06. 1277–1282. https://doi.org/10.13863/j.issn1001-4454.2019.06.013

31. Ye K, Han Y, Mao P, Wang Z, Huang J, Luan H, et al. 2019. Comparative study on toxicity of Aconiti Kusnezoffii Radix Cocta formula granule and decoctum on H9c2 myocardial cell. Chinese Journal of Modern Applied Pharmacy. 36:13. 1622–1626. https://doi.org/10.13748/j.cnki.issn1007-7693.2019.13.005

32. Feng Q, Luan YF, Sun R, Yan M. 2014; Experimental study on “dose- time- toxicity” relationship of cardiotoxicity induced by multiple doses Aconite water extract on mice. Chinese Journal of Pharmacovigilance. 11:10. 592–595.

33. 唐恬赵婷. 2016. 附子及其炮制品对大鼠心脏毒性的影响. 中国中医急症. 25:12. 2286–2290. https://doi.org/10.3969/j.issn.1004-745X.2016.12.023

34. Zhang X, Song Y, Yang Y, He S, Xie X. 2015; Studies on the acute toxicity of Aconitum Carmichaeli Debx processed products decoction in heart of beagle dogs. Chinese Journal of Ethnomedicine and Ethnopharmacy. 24:16. 21–23.

35. You J, Zhou ZX, Huang F, Han LT, Li JJ, Wang Q, Dong XY. 2015. Effects of long term toxicity of Asarum on SD rat’s ECG and myocardial enzyme spectrum. Journal of Hubei University of Chinese Med icine. 17:4. 1–3. https://doi.org/10.3969/j.issn.1008-987x.2015.04.01

36. 明海霞 , 陈彦文 , 王强 , 黄世佐 . 2015. 单叶细辛对家兔心肌的急性毒性作用. Chinese Journal of Gerontology. 5:5. 1337–1339. https://doi.org/10.3969/j.issn.1005-9202.2015.05.087

37. 郭志达 , 吉小莉 . 2000; 中药蜈蚣对大鼠心脏毒性作用的初步研究. Chinese Journal of Clinical Pharmacology and Therapeutics. 5:3. 278

38. Wu JX, Yu GR, Wang BY, Zhong DS, Huang DJ. 1994; Effects of Viscum coloration flavonoids on fast response action potentials of hearts. Acta Pharmacologica Sinica. 15:2. 169–72.

39. Peng W, Wang L, Fu CM, Wu MQ, Tu H, Fu S. 2021. Study on toxicity -efficacy dualism of Fuzi (附子) regarding its anti-heart failure effect and cardiotoxicity: Based on network pharmacology. Journal of Traditional Chinese Medicine. 62:6. 523–529. https://doi.org/10.13288/j.11-2166/r.2021.06.013

40. Li L, Sun ML, Zhang SY, Xue F, Zhang J, Xu TH, et al. 2014. Active ingredient research of antiarrhythmic medicines. World Chinese Medicine. 9:9. 1241–1243. https://doi.org/10.3969/j.issn.1673-7202.2014.09.039