Akimoto K, Sano N, Takikawa H
Department of Medicine, Teikyo University School of Medicine, 173-8605, Itabashi-ku, Tokyo, Japan.
Steroids. 2001 Sep;66(9):701-5. doi: 10.1016/s0039-128x(01)00102-7.
Biliary organic anion excretion is mediated by an ATP-dependent primary active transporter, multidrug resistance protein 2. On the other hand, a multiplicity of canalicular organic anion transport has been suggested. Ursodeoxycholic acid, the 7beta-epimer of chenodeoxycholic acid, is clinically used for various hepatobiliary diseases. In our previous study, the contribution of multidrug resistance protein 2 for biliary excretion of taurine-conjugated bile acid sulfates depended on the numbers of hydroxyl residue. Therefore, to further examine the effect of hydrophobicity on the substrate specificity of multidrug resistance protein 2, we examined the effect of bile acid conjugates and organic anions on biliary excretion of tauroursodeoxycholate-3-sulfate, taurine and sulfonate-conjugated ursodeoxycholic acid, in rats. Biliary tauroursodeoxycholate-3-sulfate excretions was markedly delayed in Eisai hyperbilirubinemic rats. Taurolithocholate-3-sulfate inhibited but ursodeoxycholate-3,7-disulfate did not affect biliary tauroursodeoxycholate-3-sulfate excretion. Biliary tauroursodeoxycholate-3-sulfate excretion was inhibited by sulfobromophthalein, but was not inhibited by dibromosulfophthalein and cefpiramide. These findings indicate that tauroursodeoxycholate-3-sulfate is very specific for multidrug resistance protein 2.
胆汁有机阴离子的排泄由一种ATP依赖的原发性主动转运体——多药耐药蛋白2介导。另一方面，已有研究提示胆小管存在多种有机阴离子转运。熊去氧胆酸是鹅去氧胆酸的7β-差向异构体，临床上用于治疗各种肝胆疾病。在我们之前的研究中，多药耐药蛋白2对牛磺酸结合型胆汁酸硫酸盐胆汁排泄的贡献取决于羟基残基的数量。因此，为了进一步研究疏水性对多药耐药蛋白2底物特异性的影响，我们检测了胆汁酸结合物和有机阴离子对大鼠牛磺熊去氧胆酸-3-硫酸盐、牛磺酸和磺酸盐结合型熊去氧胆酸胆汁排泄的影响。在卫材高胆红素血症大鼠中，胆汁中牛磺熊去氧胆酸-3-硫酸盐的排泄明显延迟。牛磺石胆酸-3-硫酸盐可抑制胆汁中牛磺熊去氧胆酸-3-硫酸盐的排泄，但熊去氧胆酸-3,7-二硫酸盐则无此作用。磺溴酞钠可抑制胆汁中牛磺熊去氧胆酸-3-硫酸盐的排泄，但二溴磺酞钠和头孢匹胺则无此作用。这些结果表明，牛磺熊去氧胆酸-3-硫酸盐对多药耐药蛋白2具有高度特异性。
