A decrease in the human ether‐a‐go‐go‐related gene (hERG/KCNH2)‐related channel has been linked to intrauterine fetal death. The formation of cytochrome P450 (CYP) 3A‐mediated progesterone metabolites, 6‐beta‐hydroxy‐progesterone (6β‐OHP) and 16α‐hydroxy‐progesterone (16α‐OHP), is variable among adults and differs from fetal metabolism. The primary objective of this study was to assess the potential for progesterone metabolites to inhibit hERG‐related current and predict QTc intervals. Whole‐cell voltage‐clamp electrophysiology was performed on human embryonic kidney 293 cells stably expressing hERG exposed to progesterone or metabolites. Both 6β‐OHP and 16α‐OHP positively shifted the voltage dependence of activation relative to vehicle from ‐4.0 ± 0.8 to ‐0.3 ± 0.8 mV, P < .01; and 1.0 ± 0.6 mV, P < .01, respectively. In addition, 6β‐OHP decreased maximal outward tail currents from 49.4 ± 4.9 to 32.5 ± 4.1 pA/pF, P < 0.01, and reduced the expression of fully glycosylated hERG by 42%. Healthy female subjects were administered progesterone 400 mg orally for 7 days, ibutilide 0.003 mg/kg was infused, and serial electrocardiograms and blood samples collected. Relationships between rate‐corrected QT intervals (QTcI) with circulating hormones and metabolites were assessed. The 6β‐OHP and 16α‐OHP metabolites were independent predictors of QTcI intervals prior to and following ibutilide administration. In conclusion, the progesterone metabolites formed via CYP3A cause inhibitory effects on hERG channels and predict QTcI intervals in healthy women pretreated with progesterone. Further study into maternal and fetal exposure to these metabolites and potential to prolong cardiac repolarization is warranted.

中文翻译：

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黄体酮代谢物抑制人类 Ether-a-go-go-相关基因并预测 QT 间期长度

人类 ether-a-go-go 相关基因 ( hERG /KCNH2) 相关通道的减少与宫内胎儿死亡有关。细胞色素 P450 (CYP) 3A 介导的黄体酮代谢物 6-β-羟基-黄体酮 (6β-OHP) 和 16α-羟基-黄体酮 (16α-OHP) 的形成在成人中是可变的，并且不同于胎儿代谢。本研究的主要目的是评估孕酮代谢物抑制hERG相关电流和预测 QTc 间期的潜力。对暴露于黄体酮或代谢物的稳定表达 hERG 的人胚肾 293 细胞进行全细胞电压钳电生理学研究。6β-OHP 和 16α-OHP 均将激活相对于载体的电压依赖性从 ‐4.0 ± 0.8 正向转变为 ‐0.3 ± 0.8 mV，P< .01; 和 1.0 ± 0.6 mV，P < .01，分别。此外，6β-OHP 将最大外向尾电流从 49.4 ± 4.9 降低到 32.5 ± 4.1 pA/pF，P< 0.01，并且将完全糖基化的 hERG 的表达降低了 42%。健康女性受试者口服黄体酮 400 mg，连续 7 天，输注伊布利特 0.003 mg/kg，并连续采集心电图和血样。评估了频率校正 QT 间期 (QTcI) 与循环激素和代谢物之间的关系。6β-OHP 和 16α-OHP 代谢物是伊布利特给药前后 QTcI 间期的独立预测因子。总之，通过 CYP3A 形成的黄体酮代谢物对 hERG 通道产生抑制作用，并预测经黄体酮预处理的健康女性的 QTcI 间期。有必要进一步研究母体和胎儿接触这些代谢物以及延长心脏复极化的可能性。