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.
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
Classification of disease
Medicinal herbal formulas
Yield (%)
Original
Endocrine and metabolic disorders
Bangpungtongseong-san
17.7
Donguibogam
Mental and behavioural disorders
Gamisoyo-san
26.8
Bangyakhappyeon
Guibi-tang
24.3
Donguibogam
Chengsimyeunjaeum
13.0
Donguibogam
Cheonwangbosim-dan
21.3
Donguibogam
Buhnsimgieum
14.5
Bangyakhappyeon
Respiratory diseases
Hyangso-san
13.4
Donguibogam
Gyeji-tang
9.8
Donguibogam
Mahwang-tang
4.5
Donguibogam
Gumiganghwal-tang
22.8
Donguibogam
Sosiho-tang
22.9
Donguibogam
Saengmaek-san
26.5
Donguibogam
Samsoeum
18.6
Donguibogam
Socheongryong-tang
21.7
Donguibogam
Insampaedok-san
24.3
Donguibogam
Digestive diseases
Yeongyechulgam-tang
12.7
Donguibogam
Hyangsayukgunja-tang
12.9
Donguibogam
Gwakhyangjeonggi-san
12.8
Donguibogam
Maekmundong-tang
9.2
Donguibogam
Samryeongbaechul-san
14.1
Donguibogam
Bojungikgi-tang
25.4
Donguibogam
Banhabakchulcheonma-tang
17.6
Donguibogam
Samchulgeonbi-tang
24.5
Donguibogam
Pyeongwi-san
23.4
Donguibogam
Banhasasim-tang
14.9
Donguibogam
Hyangsapyeongwi-san
18.7
Donguibogam
Naeso-san
11.9
Donguibogam
Yijung-tang
24.8
Donguibogam
Yijin-tang
18.5
Donguibogam
Bulwhangeumjeionggi-san
12.4
Bangyakhappyeon
Musculoskeletal and joint diseases
Oyaksungi-san
24.4
Donguibogam
Dangguisu-san
16.9
Donguibogam
Jakyak gamcho-tang
19.3
Donguibogam
Daeyoung-jeon
27.5
Bangyakhappyeon
Galgeun-tang
12.6
Euihakipmun
Ojeok-san
21.0
Donguibogam
Genitourinary diseases
Yukmijihwang-tang
27.0
Yihaksimo
Oryeong-san
22.7
Donguibogam
Gyejibokryeong-hwan
11.8
Donguibogam
Palmijihwang-hwan
24.7
Donguibogam
Onkyung-tang
30.6
Donguibogam
Yongdansagan-tang
18.5
Donguibogam
Paljung-san
9.3
Donguibogam
Wiryeong-tang
12.5
Donguibogam
Gamisoyo-san
19.4
Donguibogam
Jaeumganghwa-tang
20.8
Donguibogam
Hwanglyeonhaedok-tang
17.1
Donguibogam
Palmul-tang
25.9
Donguibogam
Symptoms, signs and abnormal clinical and laboratory findings, NEC (not elsewhere classified)
Sagunja-tang
22.3
Donguibogam
Sibjeondaebo-tang
22.9
Donguibogam
Ssanghwa-tang
25.5
Donguibogam
Samul-tang
33.3
Donguibogam
참고문헌
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
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