A Receptor-Independent Effect of Estrone Sulfate on the hERG Channel

Abstract

Abstract. We recently reported that physiological concentrations of 17β-estradiol partially down-regulate cardiac rapidly-activating delayed rectifier K + currents (hERG currents) independently of estrogen-receptor signaling. To determine if other estrogens have the same effect as that of 17β-estradiol, we investigated receptor-independent effects of estrone, estrone 3-sulfate, and estriol on hERG currents in patch-clamped estrogen-negative HEK293 cells. Only estrone 3-sulfate partially suppressed hERG currents in a receptor-independent manner by modifying the gating. The concentration-dependence of estrone 3-sulfate revealed that physiological levels of circulating estrone 3-sulfate can modulate hERG currents to the maximal extent in both women and men at any age.Female gender is an independent risk factor for development of torsade de pointes (TdP) not only in congenital long QT syndromes (LQTS) but also in acquired LQTS (1, 2) resulting mostly from blockade of the human ether-a-go-go-related gene (hERG) channel (3). Actually 65% -75% of drug-induced TdP occurs in women, and is thought to be associated, at least in part, with longer baseline rate-corrected QT intervals (QT C ) in women than those in men (4).There is increasing evidence that effects of sex hormones on the ionic process underlying cardiac repolarization are important determinants of the sexrelated differences (5 -7). The shortening of the QT interval by testosterone and / or progesterone have been suggested from clinical reports and model studies. In contrast, some clinical studies imply that estrogen can increase the risks of drug-induced TdP in women. In healthy premenopausal women volunteers, the susceptibility of drug-induced QT C prolongation is exaggerated in the late follicular phase where estrogen level is the highest (8). Baseline QT C in postmenopausal women who are currently taking an only estrogen-replacement therapy is slightly but significantly longer compared with the control population (9). In addition to the well-characterized influences of estrogen in cardiac repolarization concerning hormonal genomic actions (1, 10), we recently found that the physiological levels of 17β-estradiol (E2), the bioactive estrogen, acutely downregulates the hERG channel, resulting in QT C prolongation (11). Such effects of E2 are independent of the estrogen-receptor signaling, and interaction between aromatic rings of E2 and F656 hERG may be important for the effect (11).Despite of these intensive studies, underlying mechanisms for a contribution of estrogen to arrhythmogenicity remains to be unclear: for example, It has been shown that propensity to drug-induced TdP does not decline after menopause in women who have very low levels of endogenous ovarian estrogen including E2 (12). Because the hERG suppression by E2 is independent of the estrogen-receptor signaling (11), it is possible that other estrogens suppress hERG currents as E2 does. However there have been no reports as to the ability of other estrogens to modulate hERG currents acutely.To ...

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Acute Effects of Female Hormones on Cardiac Ion Channels and Cardiac Repolarization

“…This is consistent with the less clear impact of circulating estrogen on fluctuation of female baseline QT C intervals during the menstrual cycle than that of progesterone (21,28,30). Very recently, we found that estrone 3-sulfate at physiological concentrations in both women and men at any ages can suppress hERG currents with the maximal extent of effectiveness (48).…”

Sex Hormones and the QT Interval: A Review

“…[29][30][31][32][33][34] Testosterone decreases calcium channel current and increases potassium channel current and may shorten the QT interval through these mechanisms. For example, in the guinea pig model, administration of 100 nM of testosterone caused dose-dependent shortening of the action potential duration through suppression of I Ca,L channels and enhancement of I Ks channels in ventricular myocytes.…”

Estrogen metabolism by the equine embryo proper during the fourth week of pregnancy

“…Does it represent an endpoint in metabolism of E 2 , to an inactive product, or does it serve as a source for later retrieval of an active estrogen by means of an estrogen sulfatase? A recent report provides an alternative answer based on a demonstration of a receptor-independent effect of physiological levels of E 1 S (Kakusaka et al 2009). Lastly, the presence of other forms of conjugation, accounting for about one-third of conjugates, suggests further activity on the part of the embryo proper in regulating its exposure to biologically active estrogens.…”