Cardiac Safety Assessment of Medicinal Herbal Formulas Using hERG-HEK 293 cell

Article information

J Korean Med. 2019;40(2):94-105

Publication date (electronic) : 2019 June 30

doi : https://doi.org/10.13048/jkm.19020

Susanna Choi ¹

, Oh-Bin Kwon ²

, SION Lee ²

, Chang-Seob Seo ¹

, Hyeun-Kyoo Shin ¹^,

¹Herbal Medicine Research Division, Korea Institute of Oriental Medicine

²New Drug Development Center, Daegu Gyeonbuk Medical Innovation Foundation

Correspondence to: 신현규 (Hyeun-Kyoo Shin), 대전광역시 유성구 유성대로 1672 한국한의학연구원 한약연구부, Tel: +82-42-868-9464, Fax: +82-42-864-2120, E-mail: hkshin@kiom.re.kr

Received 2019 May 16; Revised 2019 May 27; Accepted 2019 May 29.

Abstract

Objectives

The correlation between medicinal herbal formulas and a risk of cardiotoxicity has been controversial. Thus, this study investigated cardiac safety assessment of 52 most commonly used medicinal herbal formulas.

Methods

We evaluated the in vitro effects of medicinal herbal formulas on recombinant human embryonic kidney 293 (HEK 293) cell line expressing human ether-a-go-go-related gene (hERG) potassium channel.

Results and Conclusion

Our results demonstrated that all of 52 medicinal herbal formulas did not show inhibition of hERG current in hERG-HEK 293 recombinant cells. In conclusion, these safety data suggest that 52 medicinal herbal formulas were not associated with an increased risk of cardiotoxicity in hERG-HEK 293 recombinant cells.

Keywords: Medicinal herbal formulas; Korea traditional medicine; cardiac safety; cardiotoxicity; hERG potassium channel

% hERG activity=Current post compound treatmentCurrent pre compound treatment×100

Fig. 1

In vitro effects of medicinal herbal formulas used to treat endocrine and metabolic diseases on the hERG current in hERG-HEK 293 recombinant cells. Panel A and B show the dose-response curve of the positive control, Quinidine (panel A, 30 – 0.1 μM) and Bangpungtongseong-san (panel B, 400 – 1.6 μg/ml) in HEK 293 cells. Data are the mean ± SEM (n=3).

Fig. 2

In vitro effects of medicinal herbal formulas used to treat mental and behavioural disorders on the hERG potassium channel in hERG-HEK 293 recombinant cells. Panel A – E show the dose-response curve of Gamisoyo-san (panel A, 400 – 1.6 μg/ml), Guibi-tang (panel B, 400 – 1.6 μg/ml), Chengsimyeunjaeum (panel C, 400 – 1.6 μg/ml), Cheonwangbosim-dan (panel D, 400 – 1.6 μg/ml) and Buhnsimgieum (panel E, 400 – 1.6 μg/ml) in hERG-HEK 293 recombinant cells. Data are the mean ± SEM (n=3).

Fig. 3

In vitro effects of medicinal herbal formulas used to treat musculoskeletal and joint diseases on the hERG potassium channel in hERG-HEK 293 recombinant cells. Panel A – F show the dose-response curve of Oyaksungi-san (panel A, 400 – 1.6 μg/ml), Dangguisu-san (panel B, 400 – 1.6 μg/ml), Jakyak gamcho-tang (panel C, 400 – 1.6 μg/ml), Daeyoung-jeon (panel D, 400 – 1.6 μg/ml), ), Galgeun-tang (panel E, 400 – 1.6 μg/ml) and Ojeok-san (panel F, 400 – 1.6 μg/ml) in hERG-HEK 293 recombinant cells. Data are the mean ± SEM (n=3).

Fig. 4

In vitro effects of medicinal herbal formulas used to treat respiratory diseases on the hERG potassium channel in hERG-HEK 293 recombinant cells. Panel A – I show the dose-response curve of Hyangso-san (panel A, 400 – 1.6 μg/ml), Gyeji-tang (panel B, 200 – 0.8 μg/ml), Mahwang-tang (panel C, 400 – 1.6 μg/ml), Gumiganghwal-tang (panel D, 400 – 1.6 μg/ml), Sosiho-tang (panel E, 400 – 1.6 μg/ml), Saengmaek-san (panel F, 400 – 1.6 μg/ml), Samsoeum (panel G, 400 – 1.6 μg/ml), Socheongryong-tang (panel H, 400 – 1.6 μg/ml) and Insampaedok-san (panel I, 400 – 1.6 μg/ml) in hERG-HEK 293 recombinant cells. Data are the mean ± SEM (n=3).

Fig. 5

In vitro effects of medicinal herbal formulas used to treat digestive diseases on the hERG potassium channel in hERG-HEK 293 recombinant cells. Panel A – O show the dose-response curve of Yeongyechulgam-tang (panel A, 400 – 1.6 μg/ml), Hyangsayukgunja-tang (panel B, 400 – 1.6 μg/ml), Gwakhyangjeonggi-san (panel C, 400 – 1.6 μg/ml), Maekmundong-tang (panel D, 400 – 1.6 μg/ml) and Samryeongbaechul-san (panel E, 400 – 1.6 μg/ml), Bojungikgi-tang (panel F, 400 – 1.6 μg/ml), Banhabakchulcheonma-tang (panel G, 400 – 1.6 μg/ml), Samchulgeonbi-tang (panel H, 400 – 1.6 μg/ml), Pyeongwi-san (panel I, 400 – 1.6 μg/ml), Banhasasim-tang (panel J, 400 – 1.6 μg/ml), Hyangsapyeongwi-san (panel K, 400 – 1.6 μg/ml), Naeso-san (panel L, 400 – 1.6 μg/ml), Yijung-tang (panel M, 400 – 1.6 μg/ml), Yijin-tang (panel N, 400 – 1.6 μg/ml) and Bulwhangeumjeionggi-san (panel O, 400 – 1.6 μg/ml) in hERG-HEK 293 recombinant cells. Data are the mean ± SEM (n=3).

Fig. 6

In vitro effects of medicinal herbal formulas used to treat genitourinary diseases on the hERG potassium channel in hERG-HEK 293 recombinant cells. Panel A – L show the dose-response curve of Yukmijihwang-tang (panel A, 400 – 1.6 μg/ml), Oryeong-san (panel B, 400 – 1.6 μg/ml), Gyejibokryeong-hwan (panel C, 200 – 0.8 μg/ml), Palmijihwang-hwan (panel D, 400 – 1.6 μg/ml), Onkyung-tang (panel E, 400 – 1.6 μg/ml), Yongdansagan-tang (panel F, 400 – 1.6 μg/ml), Paljung-san (panel G, 200 – 0.8 μg/ml), Wiryeong-tang (panel H, 400 – 1.6 μg/ml) Gamisoyo-san (panel I, 400 – 1.6 μg/ml), Jaeumganghwa-tang (panel J, 400 – 1.6 μg/ml), Hwanglyeonhaedok-tang (panel K, 400 – 1.6 μg/ml) and Palmul-tang (panel L, 400 – 1.6 μg/ml) in hERG-HEK 293 recombinant cells. Data are the mean ± SEM (n=3).

Fig. 7

In vitro effects of medicinal herbal formulas used to treat symptoms, signs and abnormal clinical and laboratory findings, NEC (not elsewhere classified) on the hERG potassium channel in hERG-HEK 293 recombinant cells. Panel A – D show the dose-response curve of Sagunja-tang (panel A, 400 – 1.6 μg/ml), Sibjeondaebo-tang (panel B, 400 – 1.6 μg/ml), Ssanghwa-tang (panel C, 400 – 1.6 μg/ml) and Samul-tang (panel D, 400 – 1.6 μg/ml) in hERG-HEK 293 recombinant cells. Data are the mean ± SEM (n=3).

Table 1

Medicinal herbal formulas of target diseases

References

1. Lee KB, Park YC, Lee SD. Characteristics of Toxicity Occurring in Outpatients at Korean Medical Clinics in Korean. J Korean Med 2016;37(10):135–150.

2. Park YC, Park HM, Lee SD. Inducible mechanisms for hepatotoxicity caused by traditional korean medicines in a view of toxicology. J Korean Oriental Med 2011;32(4):48–67.

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

4. Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature 2006;440(7083):463–9.

5. Kratz JM, Grienke U, Scheel O, Mann SA, Rollinger JM. Natural products modulating the hERG channel: hearthaches and hop. Nat Prod Rep 2017;34(8):957–980.

6. Lee JT. Research on Intake of Chinese Medicine by Korean Seoul: Korea Food & Drug Administration; 2006. p. 1–252.

7. Jeong WS, Shin WC, Hong IH, Choi JU, Kim YK. A survey on additional needs for herbal preparations in national health insurance service. Herbal Formula Science 2017;25(3):375–390.

8. Shin HK, Ha H, Seo CS, Lee MY. Standard herbal medicine formulary Daejeon: Korea Institute of Oriental Medicine; 2018. p. 7–869.

9. Lee SD. Toxic Concept in Oriental Medicine. Kor J Oriental Preventive Medical Society 1999;3(1):157–72.

10. Qiu LH, Zhou W, Tan HG, Tang XG, Wang YG, Ma ZC, et al. Rethinking and new perspectives on cardiotoxicity of traditional Chinese medicine. Toxicology research 2019;8(1):7–14.

11. Park YC, Lee SD. Toxicology for Herbal MedicineII Paju: Korea Reserarch Information; 2013. p. 234–7.

12. Wang LP, Shen ZB, Tang CP. Progress on the effect and mechanisms of effective components of traditional Chinese medicine on cardiomyocyte toxicity. J Guangdong Pharm Univ 2018;34(2):249–253.

13. Chen YF, Yu RY, Xiong YK, Xu GL, Liu Hn, et al. Application and Mechanism of Traditional Chinese Medicine in Prevention and Treatment of Adriamycin-induced Cardiotoxicity. Chinese Journal of Experimental Traditional Medical Formulae 2018;24(23):207–17.

14. Kim JC, Lee KM, Byun BH, Lim SC, Jung TY. Inhibitory Effects of Sophora flavescens on the Hepatic & Renal Side Effects of Chemotherapy by Cisplatin. Korean J Acupunct 2005;22(3):165–174.

15. Shin MK, Hwang HJ, Kim SC, Byun JS. Effect of Banhasasim-tang on the Cardiac Toxicity and clinical symptom induced by Doxorubicin. Korean J Orient Med Prescr 2002;10(1):131–142.

16. Chen LL, Zhang H, Jiang XG, Wang XY. Research Progress on Molecular Mechanisms of Traditional Chinese Medicine Active Ingredients on Antagonizing Cardiotoxicity of Chemotherapeutics. J Tradit Chin Med 2013;40(11):2387–2391.

17. Li YY, Sun HY, Jiang ZS, Pan ZY. Research on The Prevention and Treatment of Cardiac Toxicity of Antitumor Drugs in Traditional Chinese Medicine. Chinese Journal of Basic Medicine in Traditional Chinese Medicine 2018;24(11):1602–1606.

18. Kramer J, Obejero-Paz CA, Myatt G, Kuryshev YA, Brueining-Wright A, Verducci JS, et al. MICE models: superior to the HERG model in predicting Torsade de Pointes. Sci Rep 2013;3:2100.

Article information Continued