Aim

P-glycoprotein (P-gp) plays a critical role in the excretion of xenobiotics into bile. Previous studies have demonstrated that prolactin (PRL) regulates biotransformation and bile salt transport. Here we investigate whether the capability of the liver to transport xenobiotics into bile is altered in hyperprolactinemic states studying the modulation of hepatic P-gp by PRL.

Methods

We used lactating post-partum rats (PP), as a model of physiological hyperprolactinemia (15 and 21 days after delivery: PP15 and PP21, respectively), and ovariectomized rats treated with PRL (300 μg/day, 7 days, via osmotic minipumps, OVX + PRL). Hepatic P-gp expression and activity were evaluated by western blotting and using rhodamine 123 as substrate in vivo, respectively. Since P-gp is encoded by Mdr1a and Mdr1b in rodents, we quantified their expression by qPCR in primary hepatocyte cultures exposed to 0.1 μg/ml of PRL after 12 h. To further study the mechanism of hepatic P-gp modulation by PRL, hepatocytes were pretreated with actinomycin D and then exposed to PRL (0.1 μg/ml) for 12 h.

Key findings

We found increased hepatic P-gp protein expression and activity in PP15 and OVX + PRL. Also, a significant increase in Mdr1a and Mdr1b mRNA levels was observed in primary hepatocyte cultures exposed to PRL, pointing out the hormone direct action. Actinomycin D prevented these increases, confirming a transcriptional up-regulation of P-gp by PRL.

Significance

These findings suggest the possibility of an increased biliary excretion of xenobiotics substrates of P-gp, including therapeutic agents, affecting their pharmaco/toxicokinetics in hyperprolactinemic situations.

中文翻译：

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催乳素对雌性大鼠肝脏 P-糖蛋白表达及活性的诱导作用

目标

P-糖蛋白 (P-gp) 在外源性物质排泄到胆汁中起关键作用。以前的研究表明催乳素 (PRL) 调节生物转化和胆汁盐运输。在这里，我们研究了在高泌乳素血症状态下肝脏将异生物质转运到胆汁中的能力是否会改变，以研究 PRL 对肝脏 P-gp 的调节。

方法

我们使用泌乳产后大鼠 (PP) 作为生理性高催乳素血症模型（分娩后 15 天和 21 天：分别为 PP15 和 PP21），以及用 PRL（300 μg/天，7 天，通过渗透性微型泵）治疗的卵巢切除大鼠, OVX + PRL）。分别通过蛋白质印迹和使用罗丹明 123 作为体内底物评估肝脏 P-gp 表达和活性。由于 P-gp在啮齿动物中由Mdr1a和Mdr1b编码，我们通过 qPCR 在 12 小时后暴露于 0.1 μg/ml PRL 的原代肝细胞培养物中量化它们的表达。为了进一步研究 PRL 调节肝脏 P-gp 的机制，肝细胞用放线菌素 D 预处理，然后暴露于 PRL (0.1 μg/ml) 12 小时。

主要发现

我们发现 PP15 和 OVX + PRL 中肝脏 P-gp 蛋白表达和活性增加。此外，在暴露于 PRL 的原代肝细胞培养物中观察到Mdr1a和Mdr1b mRNA 水平显着增加，表明激素直接作用。放线菌素 D 阻止了这些增加，证实了 PRL 对 P-gp 的转录上调。

意义

这些发现表明 P-gp 的异生物质底物（包括治疗剂）的胆汁排泄增加的可能性，影响了它们在高催乳素血症情况下的药物/毒代动力学。