Article Detail

Home > Article Detail
  • P-ISSN 1010-0695
  • E-ISSN 2288-3339

hERG Channel-Related Cardiotoxicity Assessment of 13 Herbal Medicines

Journal of Korean Medicine / Journal of Korean Medicine, (P)1010-0695; (E)2288-3339
2021, v.42 no.3, pp.44-55





  • Downloaded
  • Viewed

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


Reference

1

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

2

2. Shin, H. D. & Jeong, J. U. (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

3. Cho, J. H. & Yoon, H. I. Essentials of toxicology. Seoul: MIP Publishing Group. 2006:349-66.

4

4. Choi, S. N., Kwon, O. B., Lee, S. O., Seo, C. S., & Shin, H. K. (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

5. Han, D. H., Kwon, K. B., Hwang, I. J., Kim, W. K., Kim, H. C., Oh, K. S., 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

6. You, B. S., Jung, J. E., Park, J. Y., Yun, J. M., Lee, I., & Moon, B. S. (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

7. Shin, M. K., Hwang, H. J., Kim, S. C., &Byun, J. S. (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

8. Su, C. P., Wang, Q., Zhang, H. M., Ren, Y. L., Wang, W., & Guo, S. Z. (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

9. Vicente, J., Strauss, D. G., Upreti, V.V., Fossler, M.J., Sager, P. T., & 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

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

11

11. Paul, A. A., Witchel, H. J., & Hancox, J. C. (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

12. Yu, R., Li, B., Wang, Y. X., & Zhu, M. J. (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

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

14

14. Wang, T., Chen, X. N., Yu, J. H., Du, Q. Q., Zhu, J., Yang, M. Z., 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

15. Zhang, Y. H., Yan, C. C., Wang, F., Li, B. X., & Yang, B. F. (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

16. Pan, X. G., Yan, B. H., Zhou, J., Cao, X. Y., & Peng, C. (2020). Research progress of Chinese Materia Medica-induced cardiotoxicity. Progress in Pharmaceutical Sciences, 44(10), 730-742.

17

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

18. Li, M. H., Zhang, G. G., & Zhao, D. H. (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

19. Meng, H. X., Yao, M. J., Ren, J. U., & Liu, J. X. (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

20. Zhang, X. D., Yu, Y. M., Fan, C. L., & Zhang, Y. Z. (2009). The protective effects of osthol against adriamycin-induced cardiotoxicity in rats. Modern Pharmacy and Clinic, 24(6), 358-359.

21

21. Li, L., Zhuang, F. E., Yang, L., Zhang, C. L., Zhao, G. S., & Zhao, D. K. (1995). Effects of osthole on isolated guinea pig heart atria. Acta Pharmacologica Sinica, 16(3), 251-254.

22

22. Li, L., Zhuang, F. E., Zhang, C. L., Zhao, G. S., & Zhao, D. K. (1995). Effects of osthole on slow action potentials and right atria frequency. Chinese Journal of Pharmacology and Toxicology, 9(2), 108-122.

23

23. Kwak, Y. G., Kim, D. K., Ma, T. Z., Park, S. A., Park, H., Jung, Y. H., 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

24. He, Y. M., Zhong, Q. Q., Wang, K., Wang, M. R., Yang, H., & Lin, J. C. (2010). Cardiotoxicity of Ephedra to rabbit model system. Journal of Huazhong Agricultural University, 29(4), 484-488.

25

25. Hong, L. Z., Li, J. L., Chen, Y. J., & Jin, G. Y. (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

26. Gui, C., Chen, M. H., Lin, S., & Wei, Y. X. (2010). Cytotoxicity effects of shikonin on rat cardiomyocytes in vitro. Pharmacology and Clinics of Chinese Materia Medica, 26(6), 33-36.

27

27. Liu, M., Yang, C. I., Meng, & Q. X. (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

28. Kim, W. S., Lim, S. S., Kang, H. S., Choue, C. W., Kim, K. S., Song, J. S., et al. (2000). Cardiovascular aspects of aconitine poisoning. Korean Circulation Journal. 30(7), 855-860.

29

29. Zhang, L., Liu, C. A., Li, W. H., Liu, F. L., Zhai, X. Y., 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

30. Wen, Y. Y., Wang, L. P., Shen, Z. B., Zhuang, S. Q., Jiang, T., & Tang, C. P. (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

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 H9c2myocardial cell. Chinese Journal of Modern Applied Pharmacy, 36(13), 1622-1626. https://doi.org/10.13748/j.cnki.issn1007-7693.2019.13.005

32

32. Feng, Q., Luan, Y. F., Sun, R., & Yan, M. (2014). Experimental study on "dose- timetoxicity"relationship of cardiotoxicity induced by multiple doses Aconite water extract on mice. Chinese Journal of Pharmacovigilance, 11(10), 592-595.

33

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

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

35. You, J., Zhou, Z. X., Huang, F., Han, L. T., Li, J. J., Wang, Q., & Dong, X. Y. (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

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

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

38. Wu, J. X., Yu, G. R., Wang, B. Y., Zhong, D. S., & Huang, D. J. (1994). Effects of Viscum coloration flavonoids on fast response action potentials of hearts. Acta Pharmacologica Sinica, 15(2), 169-72.

39

39. Peng, W., Wang, L., Fu, C. M., Wu, M. Q., 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

40. Li, L., Sun, M. L., Zhang, S. Y., Xue, F., Zhang, J., Xu, T. H., 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

  • Downloaded
  • Viewed
  • 0KCI Citations
  • 0WOS Citations

Other articles from this issue

Recommanded Articles

상단으로 이동

Journal of Korean Medicine