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JKM > Volume 42(3); 2021 > Article
Ha, Lee, Kim, Seo, and Shin: hERG Channel-Related Cardiotoxicity Assessment of 13 Herbal Medicines

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.

%hERG activity=peak hERG tail current post-sample treatmentpeak hERG tail current pre-sample treatment×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).
jkm-42-3-44f1.gif
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

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