Cardiac toxicity of Triptergium wilfordii Hook F . may correlate with its inhibition to hERG channel

Wei Zhao; Liping Xiao; Lanying Pan; Xianfu Ke; Yanting Zhang; Dian Zhong; Jianwei Xu; Fumin Cao; Liren Wu; Yuan Chen

doi:10.1016/j.heliyon.2019.e02527

Cardiac toxicity of Triptergium wilfordii Hook F . may correlate with its inhibition to hERG channel

Heliyon. 2019 Oct 9;5(10):e02527. doi: 10.1016/j.heliyon.2019.e02527. eCollection 2019 Oct.

Authors

Wei Zhao^{1

2}, Liping Xiao^{1

2}, Lanying Pan^{1

2}, Xianfu Ke³, Yanting Zhang^{1

2}, Dian Zhong^{1

2}, Jianwei Xu^{1

2}, Fumin Cao^{1

2}, Liren Wu³, Yuan Chen^{1

2}

Affiliations

¹ Chinese Herb Medicine Division, Zhejiang Agriculture and Forestry University, 666 Wusu Street, Lin'an 311300, PR China.
² The State Key Laboratory of Subtropical Silviculture, Zhejiang Agriculture and Forestry University, 666 Wusu St, Lin'an 311300, PR China.
³ Zhejiang Key Laboratory for Laboratory Animal and Safety Research, Zhejiang Academy of Medical Sciences, PR China.

Abstract

Tripterygium wilfordii Hook F. (TWHF) is a Chinese traditional medicine with cardiac toxicities. However, the mechanism of acute cardiac toxicity is not very clear. By using patch clamp techniques, we found that 0.05 mg/ml and 0.1 mg/ml of the aqueous crude extract of TWHF inhibit 21.4 ± 1.6% and 86.7 ± 5.7% (n = 5) of hERG current Amplitudes (I_hERG) respectively. We further found that Celastrol, one of main components of TWHF, inhibits hERG with an IC₅₀ of 0.83 μM. Additional mutagenesis studies show that mutations of T623A, S624A and F656A significantly alter the inhibition and S624A has the strongest effect, supported by our docking model. Our data suggest that inhibition of hERG channel activity by Celastrol contributed to TWHF cardiotoxicity.

Keywords: Cardiology; Celastrol; Dose-response relationship; Drug binding; Natural product; Patch clamp; Pharmacology; Toxicology; Tripterygium wilfordii Hook F.; Triptolide; hERG.