title: Hydroxyzine, a first generation H(1)-receptor antagonist, inhibits human ether-a-go-go-related gene (HERG) current and causes syncope in a patient with the HERG mutation.
abstract: QT prolongation, a risk factor for arrhythmias, can result from genetic variants in one (or more) of the genes governing cardiac repolarization as well as intake of drugs known to affect a cardiac K(+) channel encoded by human ether-a-go-go-related gene (HERG). In this paper, we will report a case of drug-induced long QT syndrome associated with an H(1)-receptor antagonist, hydroxyzine, in which a mutation was identified in the HERG gene. After taking 75 mg of hydroxyzine for several days, a 34-year-old female began to experience repetitive syncope. The deleterious effect of hydroxyzine was suspected because QTc interval shortened from 630 to 464 ms after cessation of the drug. Later on, the patient was found to harbor an A614V-HERG mutation. By using the patch-clamp technique in the heterologous expression system, we examined the functional outcome of the A614V mutation and confirmed a dominant-negative effect on HERG expression. Hydroxyzine concentration-dependently inhibited both wild-type (WT) and WT/A614V-HERG K(+) currents. Half-maximum block concentrations of WT and WT/A614V-HERG K(+) currents were 0.62 and 0.52 microM, respectively. Thus, accidental combination of genetic mutation and intake of hydroxyzine appeared to have led to a severe phenotype, probably, syncope due to torsade de pointes.
authors.affiliation: Department of Cardiovascular Medicine, Shiga University of Medical Science, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sakaguchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.forename: Keiko
authors.initials: K
authors.lastname: Tsuji
authors.forename: Iori
authors.initials: I
authors.lastname: Nagaoka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Oka
authors.forename: Takashi
authors.initials: T
authors.lastname: Ashihara
authors.forename: Makoto
authors.initials: M
authors.lastname: Ito
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yumoto
authors.forename: Naoko
authors.initials: N
authors.lastname: Zenda
authors.forename: Yukei
authors.initials: Y
authors.lastname: Higashi
authors.forename: Youichi
authors.initials: Y
authors.lastname: Takeyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D006919:Hydroxyzine / Q000008:administration & dosage / Q000009:adverse effects*; D008133:Long QT Syndrome / Q000139:chemically induced; D009154:Mutation; D018408:Patch-Clamp Techniques; D010641:Phenotype; D013575:Syncope / Q000139:chemically induced*; D016171:Torsades de Pointes / Q000139:chemically induced
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; D006919:Hydroxyzine