Multispecific amphipathic substrate transport by an organic anion transporter of human liver
Multispecific amphipathic substrate transport by an organic anion transporter of human liver
复制标题
DOI：
10.1016/s0168-8278(96)80246-7
复制
发表时间：
1996-11-01
影响因子：
25.7
通讯作者：
Meier, PJ
中科院分区：
文献类型：
--
作者：
Bossuyt, X;Muller, M;Meier, PJ
背景：不同电荷的两亲性内和外源药物的肝脏摄取被认为是通过不同的载体介导的运输系统发生的，或者，一个单一的大鼠有机阴离子运输多肽（oatp）最近被证明可以介导不同电荷的两亲性底物的肝细胞摄取。目的：研究克隆的人肝脏有机阴离子转运多肽（OATP）是否也能介导不依赖于电荷和类别的肝细胞对两亲性底物的摄取。方法：向非洲爪蟾卵母细胞注射OATP-cRNA，比较表达oatp的卵母细胞和未注射（或水注射）对照卵母细胞对雌酮-3-硫酸酯、瓦巴因和有机阳离子N-（4,4-偶氮- N-戊基）-21-ajmalinium的钠依赖性摄取情况。我们的研究结果表明，OATP除了能转运溴磺胺和胆盐外，还能转运阴离子型雌酮-3-硫酸盐（Km约59 μ M）、中性型瓦巴因（K-m约5.5 mM）和阳离子型N-（4,4-偶氮-正戊基）-21-ajmalinium。对于这些化合物，OATP介导的摄取均被OATP底物牛磺酸脱氧胆酸酯顺式抑制，转运活性与注射cRNA的量有良好的相关性。结论：与大鼠肝脏OATP类似，人肝脏OATP也可以介导亲脂性两亲性有机化合物的多特异性和电荷无关的摄取，因此，OATP可能在人肝脏对药物和其他外源药物的首过清除中发挥重要作用。
Background: Hepatic uptake of differently charged amphipathic endo- and xenobiotics is thought to occur via distinct carrier-mediated transport systems, Alternatively, a single rat organic anion transporting polypeptide (oatp) has recently been demonstrated to mediate hepatocellular uptake of differently charged amphipathic substrates.Aim: To investigate whether a cloned human liver organic anion transporting polypeptide (OATP) also can mediate charge- and class-independent hepatocellular uptake of amphipathic substrates.Methods: Xenopus laevis oocytes were injected with OATP-cRNA, Sodium-independent uptake of estrone-3-sulfate, ouabain and the organic cation N-(4,4-azo-n-pentyl)-21-ajmalinium was compared in OATP-expressing and uninjected (or water injected) control oocytes,Results: Our results indicate that OATP, in addition to bromosulfophthalein and bile salts, can also transport anionic estrone-3-sulfate (Km approximate to 59 mu M), neutral ouabain (K-m approximate to 5.5 mM) and cationic N-(4,4-azo-n-pentyl)-21-ajmalinium. For each of these compounds, OATP-mediated uptake was cis-inhibited by the OATP substrate taurochenodeoxycholate and the transport activities correlated well with the amounts of cRNA injected,Conclusion: Similar to the rat liver oatp, the human liver OATP can also mediate multispecific and charge-independent uptake of lipophilic amphipathic organic compounds, Thus, OATP may play an important role in the first pass clearance of drugs and other xenobiotics by the human liver.