Sodium Pump Inhibitors In Blood Pressure Regulation

CYP 11 A1对胆固醇的侧链裂解与MBG的生物合成无关，而内源性哇巴因则是如此。先前对蟾蜍的研究（已知蟾蜍能产生蟾蜍二烯内酯）表明，给药标记胆固醇和胆烷酸，而不是胆固醇侧链裂解产物孕酮，会导致放射性标记掺入蟾蜍二烯内酯分子。由于胆汁酸的肝外合成最近已被描述，我们假设，在胎盘中，其中检测到高水平的蟾蜍二烯内酯先兆子痫，MBG也可以从胆汁酸合成。因此，我们研究了两个基因的沉默的影响，CYP 27 A1，从胆固醇合成胆甾烷酸的限速酶，和CYP 11 A1，控制胆固醇侧裂解成双烯醇酮的酶，在人类滋养层JEG-3细胞对MBG和孕酮的生产。CYP 11 A1的沉默显着降低孕酮的生产，但不影响由JAG 3细胞的MBG的生产。相反，CYP 27 A1的沉默不影响孕酮的产生，但抑制MBG的产生。因此，人滋养层细胞通过胆汁酸途径从胆固醇合成MBG。

The side-chain cleavage of cholesterol by CYP11A1 is not implicated in the biosynthesis of MBG, as it is for endogenous ouabain. Previous studies in toads, known to produce bufadienolides, demonstrated that administration of labeled cholesterol and cholanic acid, but not of the product of cholesterol side-chain cleavage, progesterone, resulted in the incorporation of a radioactive label into bufadienolide molecules. Because the extra-hepatic synthesis of bile acids has recently been described, we hypothesized that in placenta, in which high levels of bufadienolides are detected in preeclampsia, MBG could also be synthesized from bile acids. Thus, we examined the impact of silencing of two genes encoding, CYP27A1, a rate-limiting enzyme for synthesis of cholanic acid from cholesterol, and of CYP11A1, an enzyme which controls side-cleavage of cholesterol into pregnenolone, in human trophoblast JEG-3 cells on production of MBG and progesterone. Silencing of CYP11A1 markedly reduced production of progesterone but did not affect production of MBG by JAG3 cells. Silencing of CYP27A1, conversely, did not affect production of progesterone, but suppressed production of MBG. Thus, human trophoblast cells synthesize MBG from cholesterol via bile acid pathway.