Uptake, Transport and Regulation of JBP485 by PEPT1 in vitro and in vivo
Uptake, Transport and Regulation of JBP485 by PEPT1 in vitro and in vivo
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PEPT1 在体外和体内对 JBP485 的摄取、运输和调节
DOI：
10.1016/j.peptides.2011.01.019
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发表时间：
2011-04-01
期刊：
影响因子：
3
通讯作者：
Liu, Kexin
中科院分区：
文献类型：
--
作者：
Liu, Zhihao;Wang, Changyuan;Liu, Kexin
环反式4-L-羟脯氨酰-L-丝氨酸（JBP485）是一种化学合成的具有抗肝炎活性的二肽。先前的大鼠实验表明，JBP485口服后被肠道吸收良好。人类肽转运蛋白 (PEPT1) 在肠道中表达，可识别二肽和三肽等化合物。本研究的目的是确定 JBP485 是否作为肠道 PEPT1 的底物，并研究 PEPT1 摄取 JBP485 和跨上皮转运的特征。在人肠上皮细胞 Caco-2 中，JBP485 的摄取具有 pH 依赖性。 Caco-2 细胞中的甘氨酰肌氨酸（Gly-Sar，PEPT1 转运蛋白的典型底物）、JBP923（JBP485 的衍生物）和头孢氨苄（CEX，一种 β-内酰胺抗生素，也是 PEPT1 的已知底物）也显着抑制 JBP485 的摄取。 JBP485从顶端到基底外侧的跨上皮转运速率是基底外侧到顶端转运的1.84倍。在Caco-2细胞中，Gly-Sar、JBP923和CEX明显抑制JBP485转运。 JBP485 的摄取会被维拉帕米增加，但不会被环孢菌素 A (CsA) 增加，并且 Caco-2 细胞中 Zn2+ 或乙醇有毒代谢物乙醛 (AcH) 的存在会抑制 JBP485 的摄取。维拉帕米在体内增加JBP485的体内摄取，乙醇在体内减少JBP485的摄取，这与体外研究一致。与对照相比，将细胞暴露于 JBP485 24 小时后，PEFT1 mRNA 水平增强。总之，JBP485 由肠道寡肽转运蛋白 PEPT1 主动转运。这种机制可能有助于JBP485口服后被胃肠道快速吸收。 (C) 2011 Elsevier Inc. 保留所有权利。
Cyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485) is a dipeptide with anti-hepatitis activity that has been chemically synthesized. Previous experiments in rats showed that JBP485 was well absorbed by the intestine after oral administration. The human peptide transporter (PEPT1) is expressed in the intestine and recognizes compounds such as dipeptides and tripeptides. The purposes of this study were to determine if JBP485 acted as a substrate for intestinal PEPT1, and to investigate the characteristics of JBP485 uptake and transepithelial transport by PEPT1. The uptake of JBP485 was pH dependent in human intestinal epithelial cells Caco-2. And JBP485 uptake was also significantly inhibited by glycylsarcosine (Gly-Sar, a typical substrate for PEPT1 transporters), JBP923 (a derivative of JBP485), and cephalexin (CEX, a beta-lactam antibiotic and a known substrate of PEPT1) in Caco-2 cells. The rate of apical-to-basolateral transepithelial transport of JBP485 was 1.84 times higher than that for basolateral-to-apical transport. JBP485 transport was obviously inhibited by Gly-Sar, JBP923 and CEX in Caco-2 cells. The uptake of JBP485 was increased by verapamil but not by cyclosporin A (CsA) and inhibited by the presence of Zn2+ or the toxic metabolite of ethanol, acetaldehyde (AcH) in Caco-2 cells. The in vivo uptake of JBP485 was increased by verapamil and decreased by ethanol in vivo, which was consisted with the in vitro study. PEFT1 mRNA levels were enhanced after exposure of the cells to JBP485 for 24 h, compared to control. In conclusion, JBP485 was actively transported by the intestinal oligopeptide transporter PEPT1. This mechanism is likely to contribute to the rapid absorption of JBP485 by the gastrointestinal tract after oral administration. (C) 2011 Elsevier Inc. All rights reserved.