Document Detail

Blockade of hERG K(+) channel by antimalarial drug, primaquine.
MedLine Citation:
PMID:  20512476     Owner:  NLM     Status:  MEDLINE    
Lengthening of the Q-T interval and proarrhythmia are adverse effects associated with antimalarial agents. Also, lengthening of the Q-T interval is a definite outcome when patients are administered with an overdose of primaquine. Inhibition of potassium current I (Kr) and resultant QT prolongation is suggested as the reason behind drug-induced arrhythmias. The present study investigated the molecular mechanisms of voltage-dependent inhibition of human Ether-a-go-go Related Gene (hERG) delayed rectifier K(+) channels expressed in HEK-293 cells by primaquine. Primaquine inhibited hERG current in a concentration-dependent manner with the half-maximal inhibitory concentration (IC(50)) of 21.5 microM. The voltage-dependent inhibition of hERG current resulted in the activation curve to be shifted to a negative voltage after primaquine exposure in a dose-dependent manner. Blockade of hERG by primaquine was also found to be time-dependent, occurring rather rapidly. Blockade of wild-type hERG channel by primaquine was similar to those of both the S6 residue hERG mutants (F656A and Y652A) and the pore region mutants (T623A). In conclusion, these results indicate that primaquine preferentially inhibits the hERG potassium channel, but blockade of hERG channel by primaquine may not be related to the S6 residue or the pore region, but may be induced through other pathways such as binding other region or effect by drug binding receptor which indicates a need for further exploration.
Ki-Suk Kim; Hyang-Ae Lee; Shin-Woo Cha; Myung-Sang Kwon; Eun-Joo Kim
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-29
Journal Detail:
Title:  Archives of pharmacal research     Volume:  33     ISSN:  0253-6269     ISO Abbreviation:  Arch. Pharm. Res.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-31     Completed Date:  2010-09-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8000036     Medline TA:  Arch Pharm Res     Country:  Korea (South)    
Other Details:
Languages:  eng     Pagination:  769-73     Citation Subset:  IM    
Department of Pharmacology, Korea Institute of Toxicology, Daejeon, Korea.
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MeSH Terms
Antimalarials / pharmacology*
Cell Line
Dose-Response Relationship, Drug
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*,  genetics
Mutagenesis, Site-Directed
Patch-Clamp Techniques / methods
Primaquine / pharmacology*
Time Factors
Reg. No./Substance:
0/Antimalarials; 0/Ether-A-Go-Go Potassium Channels; 0/KCNH1 protein, human; 90-34-6/Primaquine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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