Gan L S, Yanni S, Thakker D R
Department of Drug Metabolism, Glaxo Inc., Research Triangle Park, North Carolina 27709, USA.
Pharm Res. 1998 Jan;15(1):53-7. doi: 10.1023/a:1011944602662.
The tight junctions in the intestinal epithelium represent highly specialized intercellular junctions. Ranitidine, an H2-antagonist, causes a tightening of the tight junctions. Hence, we have investigated the effect of ranitidine and other H2-antagonists on the function of the intestinal tight junctions.
Effect of the H2-antagonists on the tight junctions has been investigated using the transepithelial electrical resistance (TEER) and the transport of mannitol across the Caco-2 cell monolayers.
Four different H2-antagonists caused an increase in the TEER across the Caco-2 cell monolayers, accompanied by a decrease in the permeability for mannitol. The effect was concentration-dependent and saturable. Ranitidine and famotidine, caused a decrease in their own transport rate across the Caco-2 cells. Ranitidine competitively inhibited the increase in TEER caused by famotidine, whereas compounds which represent molecular fragments of ranitidine had no effect. The relative potency of the four H2-antagonists in causing an increase in the TEER correlated inversely with the oral bioavailability of these compounds in humans.
We hypothesize that the H2-antagonists exert their effect on the tight junctions of Caco-2 cells by modulation of interactions among proteins associated with the tight junctional complex.
肠上皮中的紧密连接代表高度特化的细胞间连接。H2拮抗剂雷尼替丁可导致紧密连接收紧。因此，我们研究了雷尼替丁和其他H2拮抗剂对肠紧密连接功能的影响。
使用跨上皮电阻（TEER）和甘露醇跨Caco-2细胞单层的转运来研究H2拮抗剂对紧密连接的影响。
四种不同的H2拮抗剂导致Caco-2细胞单层的TEER增加，同时甘露醇的通透性降低。该效应呈浓度依赖性且具有饱和性。雷尼替丁和法莫替丁导致它们自身跨Caco-2细胞的转运速率降低。雷尼替丁竞争性抑制法莫替丁引起的TEER增加，而代表雷尼替丁分子片段的化合物则无作用。四种H2拮抗剂引起TEER增加的相对效力与这些化合物在人体内的口服生物利用度呈负相关。
我们假设H2拮抗剂通过调节与紧密连接复合物相关的蛋白质之间的相互作用，对Caco-2细胞的紧密连接发挥作用。
