Abstract 289: Receptor-independent Effects of Estrogen on the HERG Channel Predispose Women to Drug-induced Arrhythmias.
Females gender itself is a risk factor for drug-induced torsades de pointes (TdP) arrhythmia which is associated with QT prolongation caused by blockade of human ether-a-go-go related gene (hERG) currents. Despite long-time vigorous efforts, the underlying mechanism for the gender difference remains unknown. Because drug-induced QT prolongation and TdP risk exhibit dynamic changes according to the cyclic alteration of ovarian steroids level in adult women, ovarian steroids may rapidly influence cardiac repolarization. We here found that the most bioactive estrogen, 17beta-estradiol (E2), acutely delayed cardiac repolarization within the physiological serum level (0.1–1 nmol/L). E2 slightly but significantly suppressed hERG currents (IC50 = 0.7 nmol/L) by modifying channel gating kinetics. Mutagenesis study showed the interaction of E2 with a common drug-binding site at the inner pore-cavity. Furthermore, E2 increased sensitivity of hERG blockade by a blocker, E4031. The lack of effects of testosterone on hERG currents and E4031-sensitivity implicates the critical role of aromatic centroid present in E2 but not in testosterone, which is supported by data from aromatase-null mice that cannot produce aromatized estrogen. The aromatase-null mice showed lower sensitivity to E4031-induced QT prolongation compared with those of wild type mice, and i.v. application of exogenous E2 (0.1 μg/kg) subsequent to E4031 administration rapidly prolonged QT intervals, indicating that aromatized estrogen emphasize the effect of E4031 on cardiac repolarization in vivo. Our study demonstrating the interaction of aromatized estrogen with the hERG channel should be applicable to diminish the risk of life-threatening, drug side effect, TdP, in females.