Structure and Function of Drug Transporters in the Intestinal and Renal Epithelial Cells

我们研究了肾刷缘膜中H^+/有机阳离子反转运体（分泌）和肠刷缘膜中H^+/二肽共转运体（吸收）等药物转运体的细胞和分子机制。1) H^+/有机阳离子反转运体和H^+/二肽共转运体的底物特异性：抗癌药物bestatin是一种含有特殊氨基酸的二肽，可通过肠刷缘膜中的H^+/二肽共转运体转运，也可通过肾刷缘膜中的H^+/有机阳离子反转运体和H^+/二肽共转运体转运。2)肾上皮细胞系LLC-PK_1中有机阳离子的跨细胞转运：四乙基铵（tetraethyllammonium， TEA）从基底外侧逐渐被细胞单层吸收，并单向转运至顶侧。降低根尖侧的pH值可促进TEA从基底侧到根尖的转运。人肠上皮细胞系Caco-2单分子层口服头孢菌素和贝司他汀的跨细胞转运：口服头孢菌素通过定位于Caco-2细胞顶膜的H^+/二肽共转运体在Caco-2细胞单分子层中积累，这些抗生素的跨基底外膜外排涉及一个特定的转运系统。4)非洲爪蟾卵母细胞中二肽转运蛋白的表达：用Caco-2细胞的poly (A)^+mRNA注射非洲爪蟾卵母细胞，观察到H^+依赖性二肽转运蛋白的表达。

We have studied the cellular and molecular mechanisms of the drug transporters such as H^+/organic cation antiporter (secretion) in the renal brush-border membranes and H^+/dipeptide cotransporter (absorption) in the intestinal brush-border membranes.1) Substrate Specificity of the H^+/Organic Cation Antiporter and H^+/Dipeptide Cotransporter : Anticancer agent bestatin, a dipeptide containing an unusual amino acid, was transported via the H^+/dipeptide cotransporter in the intestinal brushborder membranes, and via the H^+/organic cation antiporter and the H^+/dipeptide cotransporter in the renal brush-border membranes.2) Transcellular Transport of Organic Cation across Monolayers of Kidney Epithelial Cell Line LLC-PK_1 : Tetraethylammonium (TEA) was taken up progressively by the cell monolayers from the basolateral side, and was transported unidirectionally to the apical side. The basolateral-to-apical transport of TEA was stimulated by lowering pH of the apical side. The TEA efflux from the cell monolayers to the apical side caused a decrease in the intracellular pH.3)Transcellular Transport -of Oral Cephalosporins and Bestatin by Monolayers of Human Intestinal Epithelial Cell Line Caco-2 : Oral cephalosporins accumulated in the Caco-2 cell monolayers via the H^+/dipeptide cotransporter localized in the apical membranes and that a specific transport system was involved in the efflux of these antibiotics across the basolateral membranes.4)Expression of Dipeptide Transporters in Xenopus Oocytes : The expression of H^+-dependent dipeptide transporters was observed in Xenopus laevis oocytes injected with poly (A)^+mRNA from Caco-2 cells.