Hiraoka Hideo, Kimura Naoji, Furukawa Yumiko, Ogawara Ken-ichi, Kimura Toshikiro, Higaki Kazutaka
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushimanaka, Okayama 700-8530, Japan.
J Pharmacol Exp Ther. 2005 Jan;312(1):248-55. doi: 10.1124/jpet.104.071290. Epub 2004 Oct 1.
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 p-chlorophenylalanine, 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.
为了研究血清素（5-羟色胺，5-HT）在小肠中作为一种重要的神经递质和激素/旁分泌因子，对P-糖蛋白（P-gp）转运活性的作用，我们通过腹腔注射对氯苯丙氨酸（5-HT生物合成中色氨酸羟化酶的特异性抑制剂）制备了5-HT耗竭的大鼠，并检测了P-gp底物奎尼丁的肠道转运情况。在体外转运研究中，尽管分泌性转运仍占主导，但在5-HT耗竭条件下，奎尼丁在大鼠空肠的分泌性和吸收性方向的转运均显著增强。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途径增强。这可能是由于5-HT耗竭条件下紧密连接变松。电压钳技术清楚地表明，5-HT耗竭也增强了奎尼丁通过跨细胞途径的分泌性转运。此外，5-HT耗竭增加了大鼠空肠中维拉帕米敏感的奎尼丁分泌性转运。这些结果表明，在5-HT耗竭条件下，奎尼丁通过P-gp的分泌性转运显著增强。5-HT耗竭并未改变P-gp功能所需能量来源ATP的水平、大鼠空肠湿重以及大鼠空肠黏膜中的总蛋白水平，但显著诱导了大鼠空肠刷状缘膜中P-gp的表达，这部分解释了5-HT耗竭条件下P-gp活性增强的原因。
