Transport of the soy isoflavone daidzein and its conjugative metabolites by the carriers SOAT, NTCP, OAT4, and OATP2B1
Transport of the soy isoflavone daidzein and its conjugative metabolites by the carriers SOAT, NTCP, OAT4, and OATP2B1
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DOI：
10.1007/s00204-014-1379-3
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发表时间：
2015-12-01
影响因子：
6.1
通讯作者：
Soukup, Sebastian T.
中科院分区：
文献类型：
--
作者：
Grosser, Gary;Doering, Barbara;Soukup, Sebastian T.
大豆异黄酮（IF）是植物雌激素，与雌激素受体相互作用。它们被葡萄糖醛酸转移酶和磺基转移酶广泛代谢，导致其雌激素活性的调节。可以假设，这种生物转化也有一个至关重要的影响，通过主动或被动的细胞转运机制的IF的摄取，但很少有人知道IF II相代谢物进入细胞的运输。因此，使用用五种人候选载体转染的HEK 293细胞系，即，有机阴离子转运蛋白OAT 4、钠依赖性有机阴离子转运蛋白（SOAT）、Na+-牛磺胆酸盐共转运多肽（NTCP）、顶端钠依赖性胆汁酸转运蛋白ASBT和有机阴离子转运多肽OATP 2B 1。通过UHPLC-DAD监测细胞摄取。DAI单硫酸盐通过载体NTCP和SOAT以钠依赖性方式转运，而OAT 4-HEK 293细胞显示这些化合物的部分钠依赖性转运。相比之下，DAI-7，4 '-二硫酸盐仅被NTCP-HEK 293细胞摄取。DAI-7-葡糖苷酸（而非DAI-4 '-葡糖苷酸）仅通过OATP 2B 1以钠非依赖性方式转运。DAI-7-葡糖苷酸-4 '-硫酸盐、DAI-7-葡糖苷和DAI不是任何测试载体的底物。此外，测定了DAI代谢产物对上述载体的雌酮-硫酸酯（E1 S）摄取的抑制效力。总之，人SOAT、NTCP、OATP 2B 1和OAT 4被鉴定为DAI代谢物的载体。几种代谢产物能够抑制载体依赖性E1 S摄取。这些发现可能有助于更好地了解IF的生物活性，特别是在与癌症相关的癌症中。
Soy isoflavones (IF) are phytoestrogens, which interact with estrogen receptors. They are extensively metabolized by glucuronosyltransferases and sulfotransferases, leading to the modulation of their estrogenic activity. It can be assumed that this biotransformation also has a crucial impact on the uptake of IF by active or passive cellular transport mechanisms, but little is known about the transport of IF phase II metabolites into the cell. Therefore, transport assays for phase II metabolites of daidzein (DAI) were carried out using HEK293 cell lines transfected with five human candidate carriers, i.e., organic anion transporter OAT4, sodium-dependent organic anion transporter (SOAT), Na+-taurocholate cotransporting polypeptide (NTCP), apical sodium-dependent bile acid transporter ASBT, and organic anion transporting polypeptide OATP2B1. Cellular uptake was monitored by UHPLC-DAD. DAI monosulfates were transported by the carriers NTCP and SOAT in a sodium-dependent manner, while OAT4-HEK293 cells revealed a partly sodium-dependent transport for these compounds. In contrast, DAI-7,4'-disulfate was only taken up by NTCP-HEK293 cells. DAI-7-glucuronide, but not DAI-4'-glucuronide, was transported exclusively by OATP2B1 in a sodium-independent manner. DAI-7-glucuronide-4'-sulfate, DAI-7-glucoside, and DAI were no substrate of any of the tested carriers. In addition, the inhibitory potency of the DAI metabolites toward estrone-sulfate (E1S) uptake of the above-mentioned carriers was determined. In conclusion, human SOAT, NTCP, OATP2B1, and OAT4 were identified as carriers for the DAI metabolites. Several metabolites were able to inhibit carrier-dependent E1S uptake. These findings might contribute to a better understanding of the bioactivity of IF especially in case of hormone-related cancers.