Abstract 20786: Progesterone Metabolites Alter Activation Gating of the Human Ether-a-go-go-Related Gene (hERG)-Related Current
Introduction: Progesterone (P4) at high concentrations, such as those achieved during pregnancy, may decrease the function of the voltage-gated potassium channel encoded by the human ether-a-go-go-related gene (hERG). Reductions in hERG-related current have been linked to maternal and fetal QT interval prolongation, a risk factor for arrhythmias and miscarriage. Cytochrome P450 (CYP) 3A activity is enhanced during pregnancy, is present in the fetal liver, and forms the 16α-P4 and 6β-P4 metabolites. Our objective was to assess the ability of P4 and its metabolites, formed via CYP3A isoenzymes, to alter hERG-related current.
Methods: Whole-cell, voltage-clamp experiments were performed on HEK293 cells stably expressing hERG. Acute effects were assessed by applying 10 nM, 100 nM and 1 μM of P4, 16α-P4, 6β-P4, or dimethylsulfoxide (DMSO; control) in pipette solution. Long-term effects were assessed by treating cells with P4, 16α-P4, 6β-P4, or DMSO for 24 hours. Activation gating was assessed by fitting a Boltzmann function to normalized currents.
Results: Acute application of P4 or metabolites (n=9 per group) did not reduce hERG-related current or alter activation gating (p>0.05). Long-term P4 exposure significantly reduced hERG-related current at -100 mV (maximal inward current) from a mean ± SD of -45.4 ± 14.7 pA/pF (n=19) to -30.6 ± 16.9 (n=17; p=0.03). P4 metabolites did not decrease hERG-related current following 24-hour exposure. However, a depolarizing shift in activation gating was observed (Figure) with mean ± SD voltage at half maximal activation (V50) with 16α-P4 of 3.9 ± 0.29 mV (n=18) and 6β-P4 of 1.3 ± 0.99 (n=21) versus control of -4.8 ± 1.1 (n=19) and P4 of -3.2 ± 0.71 (n=17); p<0.05.
Conclusions: P4 decreases hERG-related current at high concentrations during prolonged exposure. The P4 metabolites formed via CYP3A cause an inhibitory shift of hERG activation gating. These effects could contribute to the QT interval variability during pregnancy.
Author Disclosures: C. Egly: None. T. Shugg: None. C.W. Stamatkin: None. A.S. Patil: None. J.E. Tisdale: None. B.R. Overholser: None.
- © 2016 by American Heart Association, Inc.