Chelerythrine stimulates GSH transport by rat Mrp2 (Abcc2) expressed in canine kidney cells.
Chelerythrine stimulates GSH transport by rat Mrp2 (Abcc2) expressed in canine kidney cells.
复制标题
白屈菜红碱通过在犬肾细胞中表达的大鼠 Mrp2 (Abcc2) 刺激 GSH 转运。
DOI：
10.1152/ajpgi.00271.2003
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Kaplowitz,Neil
中科院分区：
文献类型：
--
作者：
Lou,Huan;Ookhtens,Murad;Stolz,Andrew;Kaplowitz,Neil
Rat multidrug resistant protein 2 (Mrp2; Abcc2), an ATP-driven pump located on the canalicular domain of hepatocytes, exports glutathioneS-conjugates (GS-X) and GSH among its wide variety of substrates. Previous studies have shown that chelerythrine (CHEL), a quaternary benzophenanthridine cation, reacts with GSH to form a reversible adduct under physiological conditions. Here we report that CHEL can strongly stimulate GSH efflux by Mrp2, when it is constitutively expressed in polarized canine kidney cells, thereby leading to the depletion of cellular GSH. Transepithelial transport experiments indicate that Mrp2 transports GSH and CHEL with a 1:1 stoichiometry, which can be readily inhibited by GS-bimane, a GS-X substrate for Mrp2. Moreover, CHEL can block Mrp2-mediated leukotriene C4uptake by membrane vesicles with an IC50≈ 100 μM in the presence of GSH, but notS-methyl GSH or ophthalmic acid. Thus the thiol group of GSH is required for inhibition of Mrp2 in the presence of CHEL. Our results suggest that CHEL stimulates GSH efflux by forming a reversible GS-CHEL adduct, which is transported by Mrp2 and dissociates extracellularly.
