Organic anion-transporting potypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver
Organic anion-transporting potypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver
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DOI：
10.1053/gast.2001.21176
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发表时间：
2001-02-01
期刊：
影响因子：
29.4
通讯作者：
Hagenbuch, B
中科院分区：
文献类型：
--
作者：
Kullak-Ublick, GA;Ismair, MG;Hagenbuch, B
背景与目的：肝脏对亲胆固醇有机化合物的摄取是由有机阴离子转运多肽（OATP）家族成员介导的。我们的目的是表征新型OATP-B的组织分布和肝细胞定位，并将其底物特异性与OATP-A、OATP-C和OATP 8进行比较。方法：采用北方印迹法和免疫荧光法分析OATP-B的组织分布和肝细胞定位。在注射互补RNA的非洲爪蟾卵母细胞中，测定了每个人OATP的16种底物的转运。结果：OATP-B在人肝组织中表达最丰富，定位于肝细胞的基底外侧膜。OATP-B、OATP-C和OATP 8介导溴磺酞的高亲和力摄取（K-m，分别为0.7、0.3和0.4 μ mol/L）。OATP-B还转运雌酮-3-硫酸酯，但不转运胆汁盐。尽管OATP-A、OATP-C和OATP 8显示出广泛的重叠底物特异性，但OATP 8在转运地高辛方面是独特的，并且对阴离子环肽[D-青霉胺（2，5）]脑啡肽（DPDPE;阿片受体激动剂）和BQ-123（内皮素受体拮抗剂）显示出特别高的转运活性。结论：OATP-B是位于人肝细胞基底外侧膜的第三个溴磺酞摄取系统。OATP-B、OATP-C和OATP 8占人肝脏钠非依赖性胆汁盐、有机阴离子和药物清除的主要部分。
Background & Aims: Hepatic uptake of cholephilic organic compounds is mediated by members of the organic anion-transporting polypeptide (OATP) family. We aimed to characterize the novel OATP-B with respect to tissue distribution and hepatocellular localization and to compare its substrate specificity with those of OATP-A, OATP-C, and OATP8. Methods: Tissue distribution and hepatocellular localization of OATP-B were analyzed by Northern blotting and immunofluorescence, respectively. Transport of 16 substrates was measured for each individual human OATP in complementary RNA-injected Xenopus laevis oocytes. Results: Expression of OATP-B was most abundant in human liver, where it is localized at the basolateral membrane of hepatocytes. OATP-B, OATP-C, and OATP8 mediated high-affinity uptake of bromosulphophthalein (K-m, similar to0.7, 0.3, and 0.4 mu mol/L, respectively). OATP-B also transported estrone-3-sulfate but not bile salts. Although OATP-A, OATP-C, and OATP8 exhibit broad overlapping substrate specificities, OATP8 was unique in transporting digoxin and exhibited especially high transport activities for the anionic cyclic peptides [D-penicillamine(2,5)]enkephalin (DPDPE; opioid-receptor agonist) and BQ-123 (endothelin-receptor antagonist). Conclusions: OATP-B is the third bromosulphophthalein uptake system localized at the basolateral membrane of human hepatocytes. OATP-B, OATP-C, and OATP8 account for the major part of sodium-independent bile salt, organic anion, and drug clearance of human liver.