Cardiotoxicity assessment of 31 herbal formulae by activity of hERG potassium channel in HEK 293 cells

Article information

J Korean Med. 2022;43(1):33-41
Publication date (electronic) : 2022 March 1
doi : https://doi.org/10.13048/jkm.22004
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., KM Science 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 2021 November 15; Revised 2022 February 9; Accepted 2022 February 22.

Abstract

Objectives

Drug-induced blockade of the human ether-à-go-go related gene (hERG) potassium ion channel causes acquired long QT syndrome, which is known to cause cardiac arrhythmias and be fatal. To establish safety evidence of herbal formulae, we evaluated the effects of 31 herbal formulae on hERG channel activity.

Methods

The current through hERG channel was measured by changing the membrane voltage before and after treatment with 31 herbal formulae in HEK 293 cell overexpressing hERG channel using a whole-cell patch clamp system. The current-voltage curves and the activity curves were fitted, and the hERG activity and 50% inhibitory concentration (IC50) according to each herbal formula were calculated.

Results

Chokyungjongok-tang, Oncheong-eum, and Cheongsangbangpung-tang strongly inhibited the hERG activity, with IC50 values of 67.67, 141.2, and 296.3 μg/mL, respectively. Yeonkyopaedok-san, Eunkyo-san, Ukgan-san gajinphibanha, Daegunjoong-tang (except Oryzae gluten), Insamyangyoung-tang, Banhahubak-tang, SokyungHwalhyul-tang, Jodeung-san, Hyeonggaeyeongyo-tang, and Bangkeehwangkee-tang weakly inhibited hERG activity, with IC50 values ranging from 400 to 1000 μg/mL. The other 18 herbal formulae showed very weak hERG activity inhibition of less than 50% at the highest concentration (1000 μg/mL).

Conclusion

This study provided safety information on cardiotoxicity by cardiac arrhythmia risk assessment of herbal formulae, and is expected to be a reference data for predicting the safety and risk of herbal formulae.

Supplementary Information

The contents of 31 herbal formulae

Fig. 1

Effects of 31 herbal formulae on hERG potassium channel activity in the voltage–clamp assay using HEK 293 cells. Concentration–activity curves fitted with the three parameters logistic equation for block of hERG activity by quinidine (positive control) and herbal formulae, respectively. Data are presented means ± standard error (n ≥ 4 per each point).

The extraction yield and the half–maximal inhibitory concentration (IC50) values of herbal formulas on hERG potassium channel activity

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Article information Continued

Table S1

The contents of 31 herbal formulae

Herbal formula Reference Contents of herbal medicine
Baenongsangub-tang Chunlimheonbangham Ponciri Fructus Immaturus (16.67%), Paeoniae Radix (16.67%), Platycodonis Radix (16.67%), Glycyrrhizae Radix et Rhizoma (16.67%), Zingiberis Rhizoma (16.67%), Zizyphi Fructus (16.67%)
Bangkeehwangkee-tang Geumgweyolyag Sinomeni Caulis et Rhizoma (24.39%), Astragali Radix (24.39%), Atractylodis Rhizoma Alba (14.63%), Zingiberis Rhizoma Recens (7.32%), Zizyphi Fructus (19.51%), Glycyrrhizae Radix et Rhizoma (9.76%)
Banhahubak-tang Bangyaghabpyeon Pinelliae Tuber (28.30%), Poria Sclerotium (22.64%), Magnoliae Cortex (16.98%), Perillae Folium (11.32%), Zingiberis Rhizoma (13.21%), Zizyphi Fructus (7.55%)
Cheongsangbangpung-tang Bangyaghabpyeon Angelicae Dahuricae Radix (10.92%), Forsythiae Fructus (10.92%), Platycodonis Radix (10.92%), Saposhnikoviae Radix (10.01%), Scutellariae Radix (9.54%), Cnidii Rhizoma (9.54%), Schizonepetae Spica (6.81%), Gardeniae Fructus (6.81%), Coptidis Rhizoma (6.81%), Aurantii Fructus Immaturus (6.81%), Menthae Herba (6.81%), Glycyrrhizae Radix et Rhizoma (4.08%)
Chokyungjongok-tang Bangyaghabpyeon Rehmanniae Radix Preparata (12.29%), Cyperi Rhizoma (12.29%), Angelicae Gigantis Radix (8.20%), Evodiae Fructus (8.20%), Cnidii Rhizoma (8.20%), Paeoniae Radix (6.56%), Poria Sclerotium (6.56%), Citri Unshius Pericarpium (6.56%), Corydalis Tuber (6.56%), Moutan Radicis Cortex (6.56%), Zingiberis Rhizoma (6.56%), Cinnamomi Cortex (4.09%), Artemisiae Argyi Folium (4.09%), Zingiberis Rhizoma Recens (3.28%)
Chungsanggyuntong-tang Jejungsinpyeon Scutellariae Radix (13.52%), Atractylodis Rhizoma (9.00%), Osterici seu Notopterygii Radix et Rhizoma (9.00%), Araliae Continentalis Radix (9.00%), Saposhnikoviae Radix (9.00%), Cnidii Rhizoma (9.00%), Angelicae Gigantis Radix (9.00%), Angelicae Dahuricae Radix (9.00%), Liriopis seu Ophiopogonis Tuber (9.00%), Viticis Fructus (4.51%), Chrysanthemi Indici Flos (4.51%), Chrysanthemi Indici Flos (2.71%), Glycyrrhizae Radix et Rhizoma (2.71%)
Daegunjoong-tang (without Oryzae gluten) Geumgweyolyag Zingiberis Rhizoma (50.00%), Ginseng Radix (25.00%), Zanthoxyli Pericarpium (25.00%)
Daehwajung-eum Bangyaghabpyeon Crataegi Fructus (19.99%), Hordei Fructus Germinatus (19.99%), Citri Unshius Pericarpium (15.01%), Magnoliae Cortex (15.01%), Alismatis Rhizoma (15.01%), Ponciri Fructus Immaturus (9.99%), Amomi Fructus (5.01%)
Daeshiho-tang Bangyaghabpyeon Bupleuri Radix (29.62%), Scutellariae Radix (18.52%), Paeoniae Radix (18.52%), Rhei Radix et Rhizoma (14.81%), Ponciri Fructus Immaturus (11.12%), Pinelliae Tuber (7.41%)
Dangguijakyak-san Geumgweyolyag Paeoniae Radix (18.18%), Alismatis Rhizoma (18.18%), Atractylodis Rhizoma Alba (18.18%), Poria Sclerotium (18.18%), Angelicae Gigantis Radix (13.64%), Cnidii Rhizoma (13.64%)
Dokhwalgisaeng-tang Donguibogam Araliae Continentalis Radix (8.24%), Angelicae Gigantis Radix (8.24%), Paeoniae Radix (8.24%), Loranthi Ramulus et Folium (8.24%), Rehmanniae Radix Preparata (5.88%), Cnidii Rhizoma (5.88%), Ginseng Radix (5.88%), Poria Sclerotium (5.88%), Achyranthis Radix (5.88%), Eucommiae Cortex (5.88%), Gentianae Macrophyllae Radix (5.88%), Asiasari Radix et Rhizoma (5.88%), Saposhnikoviae Radix (5.88%), Cinnamomi Cortex (5.88%), Glycyrrhizae Radix et Rhizoma (3.52%), Zingiberis Rhizoma (4.72%)
Eunkyo-san Onbyeongjobyeon Forsythiae Fructus (17.86%), Lonicerae Flos (17.86%), Arctii Fructus (10.71%), Platycodonis Radix (10.71%), Menthae Herba (10.71%), Glycine Semen Preparata (8.93%), Folium Phyllostachydis (7.14%), Schizonepetae Spica (7.14%), Glycyrrhizae Radix et Rhizoma (8.93%)
Gamiondam-tang Bangyaghabpyeon Cyperi Rhizoma (23.23%), Citri Unshius Pericarpium (11.61%), Pinelliae Tuber (7.74%), Ponciri Fructus Immaturus (7.74%), Phyllostachyos Caulis in Taeniam (7.74%), Ginseng Radix (5.81%), Poria Sclerotium (5.81%), Bupleuri Radix (5.81%), Liriopis seu Ophiopogonis Tuber (5.81%), Platycodonis Radix (5.81%), Glycyrrhizae Radix et Rhizoma (3.87%), Zingiberis Rhizoma Recens (3.87%), Zizyphi Fructus (5.16%)
Gungha-tang Bangyaghabpyeon Cnidii Rhizoma (17.64%), Pinelliae Tuber (17.64%), Poria Sclerotium (17.64%), Citri Unshius Pericarpium (8.84%), Citri Unshius Pericarpium Immaturus (8.84%), Aurantii Fructus Immaturus (8.84%), Atractylodis Rhizoma Alba (4.37%), Glycyrrhizae Radix et Rhizoma (4.42%), Zingiberis Rhizoma Recens (11.76%)
Hyeonggaeyeongyo-tang Bangyaghabpyeon Schizonepetae Spica (7.86%), Forsythiae Fructus (7.86%), Saposhnikoviae Radix (7.86%), Angelicae Gigantis Radix (7.86%), Cnidii Rhizoma (7.86%), Bupleuri Radix (7.86%), Aurantii Fructus Immaturus (7.86%), Scutellariae Radix (7.86%), Angelicae Dahuricae Radix (7.86%), Platycodonis Radix (7.86%), Paeoniae Radix (7.86%), Gardeniae Fructus (7.86%), Glycyrrhizae Radix et Rhizoma (5.62%)
Hyulbuchukeo-tang Uilimgaechag Persicae Semen (15.79%), Carthami Flos (11.84%), Angelicae Gigantis Radix (11.84%), Rehmanniae Radix Recens (11.84%), Achyranthis Radix (11.84%), Aurantii Fructus Immaturus (7.89%), Paeoniae Radix (7.89%), Cnidii Rhizoma (6.58%), Platycodonis Radix (6.58%), Bupleuri Radix (3.95%), Glycyrrhizae Radix et Rhizoma (3.95%)
Insamyangyoung-tang Bangyaghabpyeon Paeoniae Radix (15.77%), Angelicae Gigantis Radix (7.89%), Ginseng Radix (7.89%), Atractylodis Rhizoma Alba (7.89%), Astragali Radix (7.89%), Cinnamomi Cortex (7.89%), Citri Unshius Pericarpium (7.89%), Glycyrrhizae Radix et Rhizoma (7.89%), Rehmanniae Radix Preparata (5.91%), Schisandrae Fructus (5.91%), Saposhnikoviae Radix (5.91%), Polygalae Radix (3.93%), Zingiberis Rhizoma Recens (3.15%), Zizyphi Fructus (4.21%)
Jagamcho-tang Donguibogam Glycyrrhizae Radix et Rhizoma (17.43%), Rehmanniae Radix (13.09%), Cinnamomi Ramulus (13.09%), Cannabis Semen (13.09%), Liriopis seu Ophiopogonis Tuber (13.09%), Ginseng Radix (8.72%), Asini Corii Colla (8.72%), Zizyphi Fructus (6.97%), Zingiberis Rhizoma (5.81%)
Jihwangeum-ja Donguibogam Rehmanniae Radix Preparata (8.38%), Morindae Radix (8.38%), Corni Fructus (8.38%), Dendrobii Caulis (8.38%), Cistanchis Herba (8.38%), Schisandrae Fructus (8.38%), Polygalae Radix (8.38%), Poria Sclerotium (8.38%), Liriopis seu Ophiopogonis Tuber (8.38%), Aconiti Lateralis Radix Preparata (4.18%), Acori Graminei Rhizoma (4.18%), Cinnamomi Cortex (4.18%), Menthae Herba (4.18%), Zingiberis Rhizoma Recens (3.35%), Zizyphi Fructus (4.47%)
Jodeung-san Bojebonsabang Gypsum Fibrosum (21.21%), Uncariae Ramulus cum Uncus (9.09%), Citri Unshius Pericarpium (9.09%), Pinelliae Tuber (9.09%), Liriopis seu Ophiopogonis Tuber (9.09%), Poria Sclerotium (9.09%), Ginseng Radix (9.09%), Saposhnikoviae Radix (9.09%), Chrysanthmi Flos (9.09%), Glycyrrhizae Radix et Rhizoma (3.03%), Zingiberis Rhizoma Recens (3.03%)
Majain-hwan Sanghanlon Cannabis Semen (28.99%), Magnoliae Cortex (17.39%), Armeniacae Semen (14.49%), Paeoniae Radix (13.04%), Ponciri Fructus Immaturus (13.04%), Rhei Radix et Rhizoma (13.04%)
Oncheong-eum Donguibogam Angelicae Gigantis Radix (12.50%), Cnidii Rhizoma (12.50%), Paeoniae Radix (12.50%), Rehmanniae Radix Preparata (12.50%), Coptidis Rhizoma (12.50%), Scutellariae Radix (12.50%), Phellodendri Cortex (12.50%), Gardeniae Fructus (12.50%)
Sanjoin-tang Geumgweyolyag Zizyphi Semen (53.33%), Cnidii Rhizoma (13.33%), Anemarrhenae Rhizoma (13.33%), Poria Sclerotium (13.33%), Glycyrrhizae Radix et Rhizoma (6.67%)
Sogunjung-tang (without Oryzae gluten) Donguibogam Paeoniae Radix (46.98%), Cinnamomi Ramulus (27.89%), Glycyrrhizae Radix et Rhizoma (9.42%), Zingiberis Rhizoma Recens (5.65%), Zizyphi Fructus (10.05%)
Sokyunghwalhyul-tang Manbyeonghoichun Paeoniae Radix (10.11%), Angelicae Gigantis Radix (7.87%), Achyranthis Radix (6.74%), Atractylodis Rhizoma Alba (6.74%), Clematidis Radix (6.74%), Citri Unshius Pericarpium (6.74%), Persicae Semen (6.74%), Rehmanniae Radix Recens (6.74%), Cnidii Rhizoma (5.62%), Sinomeni Caulis et Rhizoma (5.62%), Osterici seu Notopterygii Radix et Rhizoma (5.62%), Saposhnikoviae Radix (5.62%), Gentianae Scabrae Radix et Rhizoma (5.62%), Angelicae Dahuricae Radix (5.62%), Poria Sclerotium (4.49%), Glycyrrhizae Radix et Rhizoma (2.25%), Zingiberis Rhizoma Recens (1.12%)
Sopung-san Oegwajeongjong Schizonepetae Spica (8.33%), Angelicae Gigantis Radix (8.33%), Sophorae Radix (8.33%), Cicadidae Periostracum (8.33%), Arctii Fructus (8.33%), Gypsum Fibrosum (8.33%), Saposhnikoviae Radix (8.33%), Rehmanniae Radix (8.33%), Atractylodis Rhizoma (8.33%), Sesami Semen Nigra (8.33%), Anemarrhenae Rhizoma (8.33%), Akebiae Caulis (4.17%), Glycyrrhizae Radix et Rhizoma (4.17%)
Taglisodog-eum Bangyaghabpyeon Lonicerae Flos (17.65%), Citri Unshius Pericarpium (17.65%), Astragali Radix (11.76%), Trichosanthis Radix (11.76%), Saposhnikoviae Radix (5.88%), Angelicae Gigantis Radix (5.88%), Cnidii Rhizoma (5.88%), Angelicae Dahuricae Radix (5.88%), Platycodonis Radix (5.88%), Magnoliae Cortex (5.88%), Gleditsiae Spina (5.88%)
Ukgan-san gajinphibanha Boyoungchwaryo Bupleuri Radix (15.87%), Pinelliae Tuber (15.87%), Atractylodis Rhizoma Alba (12.70%), Poria Sclerotium (12.70%), Angelicae Gigantis Radix (9.52%), Citri Unshius Pericarpium (9.52%), Uncariae Ramulus cum Uncus (9.52%), Cnidii Rhizoma (9.52%), Glycyrrhizae Radix et Rhizoma (4.76%)
Yeonkyopaedok-san Donguibogam Forsythiae Fructus (7.37%), Lonicerae Flos (7.37%), Schizonepetae Spica (7.37%), Saposhnikoviae Radix (7.37%), Osterici seu Notopterygii Radix et Rhizoma (7.37%), Araliae Continentalis Radix (7.37%), Bupleuri Radix (7.37%), Cnidii Rhizoma (7.37%), Aurantii Fructus Immaturus (7.37%), Platycodonis Radix (7.37%), Poria Sclerotium (7.37%), Menthae Herba (7.37%), Glycyrrhizae Radix et Rhizoma (7.37%), Zingiberis Rhizoma Recens (4.20%)
Youngseonjaetong-eum Bangyaghabpyeon Ephedrae Herba (11.26%), Paeoniae Radix (11.26%), Saposhnikoviae Radix (5.62%), Schizonepetae Spica (5.62%), Osterici seu Notopterygii Radix et Rhizoma (5.62%), Araliae Continentalis Radix (5.62%), Clematidis Radix (5.62%), Angelicae Dahuricae Radix (5.62%), Atractylodis Rhizoma (5.62%), Scutellariae Radix (5.62%), Ponciri Fructus Immaturus (5.62%), Platycodonis Radix (5.62%), Puerariae Radix (5.62%), Cnidii Rhizoma (5.62%), Angelicae Gigantis Radix (3.36%), Cimicifugae Rhizoma (3.36%), Glycyrrhizae Radix et Rhizoma (3.36%)
Yukgunja-tang Bangyaghabpyeon Pinelliae Tuber (20.17%), Atractylodis Rhizoma Alba (20.17%), Citri Unshius Pericarpium (13.46%), Poria Sclerotium (13.46%), Ginseng Radix (13.46%), Glycyrrhizae Radix et Rhizoma (6.71%), Zingiberis Rhizoma Recens (5.38%), Zizyphi Fructus (7.18%)

Fig. 1

Effects of 31 herbal formulae on hERG potassium channel activity in the voltage–clamp assay using HEK 293 cells. Concentration–activity curves fitted with the three parameters logistic equation for block of hERG activity by quinidine (positive control) and herbal formulae, respectively. Data are presented means ± standard error (n ≥ 4 per each point).

Table 1

The extraction yield and the half–maximal inhibitory concentration (IC50) values of herbal formulas on hERG potassium channel activity

Classification of diseases (KCDa) Herbal formula Yield of extract (%) IC50 value (μg/mL)
Infectiouse disease Baenongsangub-tang 26.46 > 1000
Eunkyo-san 19.96 583.76
Taglisodog-eum 24.67 > 1000

Mental and behavioural disease Jodeung-san 20.13 861.05
Sanjoin-tang 16.80 > 1000
Ukgan-san gajinphibanha 21.13 658.59

Nervous disease Chungsanggyuntong-tang 28.34 > 1000
Gamiondam-tang 22.55 > 1000

Circulatory disease Hyulbuchukeo-tang 26.72 > 1000
Jagamcho-tang 26.12 > 1000
Jihwangeum-ja 24.66 > 1000

Respiratory disease Bangkeehwangkee-tang 18.23 986.83
Yeonkyopaedok-san 23.00 410.26

Digestive disease Banhahubak-tang 11.66 840.5
Daegunjoong-tang 12.13 670.79
Daehwajung-eum 21.38 > 1000
Daeshiho-tang 25.62 > 1000
Gungha-tang 20.14 > 1000
Insamyangyoung-tang 29.84 795.4
Majain-hwan 14.81 > 1000
Sogunjung-tang 17.74 > 1000
Yukgunja-tang 22.04 > 1000

Skin and subcutaneous tissue disease Cheongsangbangpung-tang 28.20 296.29
Hyeonggaeyeongyo-tang 25.93 958.78
Oncheong-eum 24.65 141.24
Sopung-san 17.44 > 1000

Musculoskeletal and joint disease Dokhwalgisaeng-tang 22.27 > 1000
Sokyunghwalhyul-tang 26.54 857.16
Youngseonjaetong-eum 26.72 > 1000

Genitourinary disease Chokyungjongok-tang 24.02 67.67
Dangguijakyak-san 24.13 > 1000
a

KCD: Korean standard classification of diseases