title: Endoxifen, the active metabolite of tamoxifen, inhibits cloned hERG potassium channels.
abstract: The effects of tamoxifen, and its active metabolite endoxifen (4-hydroxy-N-desmethyl-tamoxifen), on hERG currents stably expressed in HEK cells were investigated using the whole-cell patch-clamp technique and an immunoblot assay. Tamoxifen and endoxifen inhibited hERG tail currents at -50mV in a concentration-dependent manner with IC50 values of 1.2 and 1.6μM, respectively. The steady-state activation curve of the hERG currents was shifted to the hyperpolarizing direction in the presence of endoxifen. The voltage-dependent inhibition of hERG currents by endoxifen increased steeply in the voltage range of channel activation. The inhibition by endoxifen displayed a shallow voltage dependence (δ=0.18) in the full activation voltage range. A fast application of endoxifen induced a reversible block of hERG tail currents during repolarization in a concentration-dependent manner, which suggested an interaction with the open state of the channel. Endoxifen also decreased the hERG current elicited by a 5s depolarizing pulse to +60mV to inactivate the hERG currents, suggesting an interaction with the activated (open and/or inactivated) states of the channels. Tamoxifen and endoxifen inhibited the hERG channel protein trafficking to the plasma membrane in a concentration-dependent manner with endoxifen being more potent than tamoxifen. These results indicated that tamoxifen and endoxifen inhibited the hERG current by direct channel blockage and by the disruption of channel trafficking to the plasma membrane in a concentration-dependent manner. A therapeutic concentration of endoxifen inhibited the hERG current by preferentially interacting with the activated (open and/or inactivated) states of the channel.
authors: Department of Physiology, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Yun Ju
authors: YJ
authors: Chae
authors: Department of Physiology, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Keon Jin
authors: KJ
authors: Lee
authors: Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Hong Joon
authors: HJ
authors: Lee
authors: Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Ki-Wug
authors: KW
authors: Sung
authors: College of Pharmacy, Integrated Research Institute of Pharmaceutical, The Catholic University of Korea, Gyeonggi-do, Republic of Korea.
authors: Jin-Sung
authors: JS
authors: Choi
authors: Department of Physiology, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Eun Hui
authors: EH
authors: Lee
authors: Department of Physiology, The Catholic University of Korea, Seoul 137-701, Republic of Korea. Electronic address: sjhahn@catholic.ac.kr.
authors: Sang June
authors: SJ
authors: Hahn
mesh_terms: D003001:Cloning, Molecular; D055724:Electrophysiological Phenomena / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D026902:Potassium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen
keywords: Channel trafficking; Endoxifen; Tamoxifen; hERG channel