Breast Cancer Resistance Protein-Mediated Efflux of Luteolin Glucuronides in HeLa Cells Overexpressing UDP-Glucuronosyltransferase 1A9
Breast Cancer Resistance Protein-Mediated Efflux of Luteolin Glucuronides in HeLa Cells Overexpressing UDP-Glucuronosyltransferase 1A9
复制标题
过表达 UDP-葡萄糖醛酸基转移酶 1A9 的 HeLa 细胞中乳腺癌抗性蛋白介导的木犀草素葡萄糖苷酸外流
DOI：
10.1007/s11095-013-1207-0
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发表时间：
2014-04
影响因子：
3.7
通讯作者：
Liu, Z
中科院分区：
文献类型：
--
作者：
Tang, L;Li, Y;Chen, W;Zeng, S;Dong, LN;Peng, XJ;Jiang, W;Hu, M;Liu, Z
目的糖醛酸苷基转移酶（UGTs）参与多酚类黄酮中葡萄糖醛酸苷的生成。本研究探讨了ugt1a9介导的木犀草素葡萄糖醛酸化及木犀草素葡萄糖醛酸外排动力学。方法利用过表达UGT1A9的hela细胞（HeLa-UGT1A9）检测乳腺癌耐药蛋白（BCRP）介导木犀草素葡萄糖醛酸苷转运的动力学。人UGT异构体用于测定葡萄糖醛酸化速率。结果sugt1a9可催化生成4种木犀草素葡糖醛酸盐，包括3种已知的单葡糖醛酸盐和1种新的3 ',4 ' -双葡糖醛酸盐。Ko143是一种有效的BCRP特异性抑制剂，可显著抑制HeLa1A9细胞中木犀草素单lucuronides的外排，并以剂量依赖的方式增加其细胞内水平。当细胞内总单lucuronides浓度大于0.07 nM时，观察到木犀草素双lucuronide形成。结论高浓度（> ~ 0.07 nM）下可检测到双lucuronide在细胞内的蓄积。推测地lucuronide的产生是木犀草素处置的代偿途径。
PurposeUDP-glucuronosyltransferases (UGTs) are responsible for the formation of glucuronides of polyphenolic flavonoids. This study investigated the UGT1A9-mediated glucuronidation of luteolin and the kinetics of luteolin glucuronide efflux.MethodHeLa cells overexpressing UGT1A9 (HeLa-UGT1A9) were used to determine the kinetics of breast cancer resistance protein (BCRP)-mediated transport of luteolin glucuronides. Human UGT isoforms were used to determine glucuronidation rates.ResultsUGT1A9 was found to catalyze the production of four luteolin glucuronides, including three known monoglucuronides and a novel 3′, 4′-diglucuronide. Ko143, a potent specific inhibitor of BCRP, significantly inhibited efflux of luteolin monoglucuronides from HeLa1A9 cells and increased their intracellular levels in a dose-dependent manner. The formation of luteolin diglucuronide was observed when intracellular concentration of total monoglucuronides went above 0.07 nM.ConclusionsIntracellular accumulation of diglucuronide was detected at high monoglucuronide concentrations (>0.07 nM). Diglucuronide production is speculated to be a compensatory pathway for luteolin disposition.