Bossuyt X, Müller M, Hagenbuch B, Meier P J
Department of Medicine, University Hospital, Zurich, Switzerland.
J Pharmacol Exp Ther. 1996 Mar;276(3):891-6.
An organic anion-transporting polypeptide that mediates sodium-independent uptake of negatively charged sulfobromophthalein and bile salts has recently been cloned from rat liver (Jacquemin et al., 1994). In this study we have extended the substrate specificity studies to neutral and positively charged organic compounds with use of the Xenopus laevis oocyte expression systems. We found that the same transporting polypeptide can also transport the neutral cardiac glycoside ouabain (apparent Km approximately 1.7mM); the endogenous steroids aldosterone (Km approximately 15nM), cortisol (Km approximately 13 microM) and dexamethasone; the anionic steroid-conjugates estrone-3-sulfate (Km approximately 4.5 microM) and estradiol-17-glucuronide (Km approximately 3.0 microM) and the exogenous amphipathic organic cation N-(4,4-azo-n-pentyl)-21-deoxyajmalinium, a permanently charged photolabile derivative of the antiarrhythmic drug N-propylajmaline. These data demonstrate that the previously cloned hepatic organic anion-transporting polypeptide can in fact transport a wide range of differently charged lipophilic organic compounds including exogenous and endogenous organic anions, neutral steroids and organic cations. Hence, a single sinusoidal (or basolateral) transporting polypeptide can account, at least in part, for charge-independent steroid and drug clearance in mammalian liver.
一种介导对带负电荷的磺溴酞和胆汁盐进行不依赖于钠的摄取的有机阴离子转运多肽，最近已从大鼠肝脏中克隆出来（雅克曼等人，1994年）。在本研究中，我们利用非洲爪蟾卵母细胞表达系统，将底物特异性研究扩展到中性和带正电荷的有机化合物。我们发现，同一种转运多肽还能转运中性强心苷哇巴因（表观Km约为1.7mM）；内源性类固醇醛固酮（Km约为15nM）、皮质醇（Km约为13μM）和地塞米松；阴离子类固醇结合物雌酮-3-硫酸盐（Km约为4.5μM）和雌二醇-17-葡糖苷酸（Km约为3.0μM）以及外源性两亲有机阳离子N-（4,4-偶氮正戊基）-21-脱氧阿马林鎓，一种抗心律失常药物N-丙基阿马林的永久带电光不稳定衍生物。这些数据表明，先前克隆的肝脏有机阴离子转运多肽实际上可以转运多种带不同电荷的亲脂性有机化合物，包括外源性和内源性有机阴离子、中性类固醇和有机阳离子。因此，单一的窦状（或基底外侧）转运多肽至少可以部分解释哺乳动物肝脏中不依赖电荷的类固醇和药物清除。
