Up-regulation of P-glycoprotein expression in small intestine under chronic serotonin-depleted conditions in rats
Up-regulation of P-glycoprotein expression in small intestine under chronic serotonin-depleted conditions in rats
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DOI：
10.1124/jpet.104.071290
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发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Higaki, K
中科院分区：
文献类型：
--
作者：
Hiraoka, H;Kimura, N;Higaki, K
为了研究小肠中重要的神经递质和激素/旁分泌剂 5-羟色胺 (5-HT) 在 P-糖蛋白 (P-gp) 转运活性中的作用，在通过腹膜内给予对氯苯丙氨酸（5-HT 生物合成中色氨酸羟化酶的特异性抑制剂）制备的 5-HT 耗尽大鼠中检查奎尼丁（P-gp 底物）的肠道转运。在体外转运研究中，在5-HT耗尽的条件下，奎尼丁穿过大鼠空肠的转运在分泌和吸收方向上均显着增强，尽管分泌转运仍然占主导地位。电生理学研究表明，奎尼丁通过被动扩散的转运可能通过细胞旁路途径得到增强。这可能是由于 5-HT 耗尽条件下紧密连接较松散。电压钳技术清楚地表明奎尼丁通过跨细胞途径的分泌转运也因 5-HT 的消耗而增强。此外，5-HT 消耗增加了大鼠空肠中维拉帕米敏感的奎尼丁分泌转运。这些结果表明，在 5-HT 耗尽的条件下，奎尼丁通过 P-gp 的分泌转运显着增强。 5-HT消耗未改变大鼠空肠粘膜中P-gp功能的能量来源ATP水平、空肠湿重和总蛋白水平，但大鼠空肠刷状缘膜中P-gp的表达显着诱导，这是5-HT消耗条件下P-gp活性增强的部分原因。
To investigate the role of serotonin (5-HT), an important neurotransmitter and hormone/paracrine agent in the small intestine, in the transport activity of P-glycoprotein (P-gp), the intestinal transport of quinidine, a P-gp substrate, was examined in 5-HT-depleted rats prepared by intraperitoneal administration of pchlorophenylalanine, a specific inhibitor of tryptophan hydroxylase in 5-HT biosynthesis. In the in vitro transport study, quinidine transport across rat jejunum was significantly enhanced in both the secretory and absorptive directions under 5-HT-depleted conditions, although the secretory transport was still predominant. The electrophysiological study suggested that the quinidine transport via passive diffusion was enhanced presumably through a paracellular route. This might be due to looser tight junctions under 5-HT-depleted conditions. The voltage-clamp technique clearly indicated that the secretory transport of quinidine through the transcellular pathway was also enhanced by the depletion of 5-HT. Furthermore, 5-HT depletion increased verapamil-sensitive secretory transport of quinidine in rat jejunum. These results indicate that the secretory transport of quinidine via P-gp was significantly enhanced under 5-HT-depleted conditions. The level of ATP, an energy source for functioning P-gp, wet weight of jejunum, and total protein level in rat jejunal mucosa were not changed by 5-HT depletion, but the expression of P-gp in the brush-border membrane of rat jejunum was significantly induced, which is partly responsible for the enhancement of P-gp activity under the 5-HT-depleted condition.