Nucleobase- and p-glycoprotein-mediated transport of AG337 in a Caco-2 cell culture model.
Nucleobase- and p-glycoprotein-mediated transport of AG337 in a Caco-2 cell culture model.
复制标题
Caco-2 细胞培养模型中 AG337 的核碱基和 p-糖蛋白介导的转运。
DOI：
10.1021/mp034012d
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发表时间：
2004
影响因子：
4.9
通讯作者：
Chen,Jiyue
中科院分区：
文献类型：
--
作者：
Hu,Ming;Chen,Jiyue
本研究旨在确定AG 337的肠道转运特征。Caco-2细胞单层用于AG 337的定向转运。结果表明，AG 337从基底侧（BL）向顶侧（AP）或分泌转运的速率始终高于AP向BL或吸收转运的速率。随着浓度从10 μM增加到75 μM，BL−AP/AP−BL比值从7.6增加到17.2，之后稳定下来。以下结果表明P-糖蛋白参与AG 337的AP流出。(1)维拉帕米完全取消了定向转运。(2)分泌运输的表观活化能较高（33千卡/摩尔）。(3)维拉帕米（63%）和双嘧达莫（35%）抑制分泌转运，但不被丙磺舒。(4)维拉帕米（232%）和双嘧达莫（41%）增强了AP到BL的转运，但丙磺舒或AP pH值的变化并没有改变。在AG 337的AP摄取中可能涉及另外的载体机制，因为（1）吸收渗透性随着浓度的增加而降低，即使分泌渗透性保持不变，（2）在含有维拉帕米和双嘧达莫的培养基中的吸收转运速率比仅含有维拉帕米的培养基低37%，在含有维拉帕米和核碱基混合物（由腺嘌呤、次黄嘌呤和黄嘌呤组成，各100 μM）的培养基中，吸收转运速率也低于仅含维拉帕米的培养基。AG 337在Caco-2细胞中的顶端转运至少部分由p-糖蛋白（流出）和转运（摄取）核酸碱基的核碱基转运蛋白介导。关键词：摄取;流出;活化能;抑制剂;吸收;分泌
This study aimed to determine the intestinal transport characteristics of AG337. Caco-2 cell monolayers were used for directional transport of AG337. The results indicated that the rate of basolateral (BL) to apical (AP) or secretory transport of AG337 was always higher than the rate of AP to BL or absorptive transport. The BL−AP/AP−BL ratio increased from 7.6 to 17.2 as the concentration increased from 10 to 75 μM and stabilized afterward. The following results suggest that the p-glycoprotein is involved in the AP efflux of AG337. (1) Verapamil completely abolished the directional transport. (2) The apparent activation energy for secretory transport was high (33 kcal/mol). (3) Secretory transport was inhibited by verapamil (63%) and dipyridamole (35%), but not by probenecid. (4) AP to BL transport was enhanced by verapamil (232%) and dipyridamole (41%), but was not altered by probenecid or an AP pH change. An additional carrier mechanism may be involved in the AP uptake of AG337 because (1) absorptive permeabilities decreased as the concentration increased even though secretory permeabilities remained the same, (2) the absorptive transport rate was 37% lower in a medium containing verapamil and dipyridamole than in a medium containing only verapamil, and (3) the absorptive transport rate was also lower in a medium containing verapamil and a nucleobase mixture (consisting of adenine, hypoxanthine, and xanthine at 100 μM each) than in a medium containing verapamil only. Apical transport of AG337 in the Caco-2 cells is mediated, at least in part, by p-glycoprotein (efflux) and a nucleobase transporter that transports (uptake) nucleic bases.Keywords: Uptake; efflux; activation energy; inhibitors; absorptive; secretory