Contributions of multiple transport mechanisms to intestinal uptake of serotonin

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Journal of pharmaceutical sciences Pub Date : 2024-11-01 DOI:10.1016/j.xphs.2024.07.020
Suguru Asaji, Yuta Funai, Yuta Seki, Ikumi Tamai, Yoshiyuki Shirasaka
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Abstract

This study aimed to analyze the contributions of multiple transport mechanisms to the intestinal uptake of serotonin (5-HT) by employing a variety of in vitro experimental techniques, focusing on organic cation transporters expressed in the gastrointestinal (GI) tract, such as SERT, PMAT, THTR2, OCT3, and OCTN2. Analysis of the concentration dependence of 5-HT uptake by Caco-2 cells revealed multi-affinity kinetics with high-affinity and low-affinity components, suggesting that multiple transporters are involved in the intestinal 5-HT uptake. Comparative analysis of transporters using Km values obtained in Xenopus oocyte expression systems suggested that SERT is responsible for the high-affinity transport, while PMAT, THTR2, and OCT3 contribute to the low-affinity transport. Further analysis indicated that the relative contributions of SERT and PMAT to the intestinal 5-HT uptake (0.01 µM) are approximately 94.9% and 1.1%, respectively. Interestingly, at the concentration of 10 µM, the reported steady-state concentration of 5-HT in the human colon, the contributions of SERT, PMAT, THTR2, and OCT3 were estimated to be approximately 37.0%, 1.0%, 18.2%, and 20.5%, respectively. In conclusion, the present study indicated that the contributions of multiple transporters to 5-HT uptake in the GI tract are dependent upon the colon luminal concentration of 5-HT.
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多种转运机制对羟色胺肠道吸收的贡献
本研究旨在采用多种体外实验技术,分析多种转运机制对5-羟色胺(5-HT)肠道摄取的贡献,重点研究胃肠道(GI)中表达的有机阳离子转运体,如SERT、PMAT、THTR2、OCT3和OCTN2。对 Caco-2 细胞摄取 5-HT 的浓度依赖性进行的分析表明,5-HT 的摄取具有高亲和力和低亲和力的多亲和力动力学,这表明有多个转运体参与了肠道 5-HT 的摄取。利用在爪蟾卵母细胞表达系统中获得的 Km 值对转运体进行的比较分析表明,SERT 负责高亲和力转运,而 PMAT、THTR2 和 OCT3 对低亲和力转运做出了贡献。进一步分析表明,SERT 和 PMAT 对肠道 5-HT 摄取(0.01 µM)的相对贡献率分别约为 94.9% 和 1.1%。有趣的是,当浓度为 10 µM(据报道 5-HT 在人体结肠中的稳态浓度)时,SERT、PMAT、THTR2 和 OCT3 的贡献率估计分别约为 37.0%、1.0%、18.2% 和 20.5%。总之,本研究表明,多种转运体对消化道 5-HT 摄取的贡献取决于结肠腔内 5-HT 的浓度。
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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
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