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首页> 外文期刊>American Journal of Physiology >Chelerythrine stimulates GSH transport by rat Mrp2 (Abcc2) expressed in canine kidney cells.
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Chelerythrine stimulates GSH transport by rat Mrp2 (Abcc2) expressed in canine kidney cells.

机译：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。

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摘要

Rat multidrug resistant protein 2 (Mrp2; Abcc2), an ATP-driven pump located on the canalicular domain of hepatocytes, exports glutathione S-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 C4 uptake by membrane vesicles with an IC50 approximately 100 microM in the presence of GSH, but not S-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.
机译：大鼠多药抗性蛋白2（Mrp2; Abcc2）是由ATP驱动的泵，位于肝细胞的小管区域，可在多种底物中输出谷胱甘肽S-结合物（GS-X）和GSH。先前的研究表明，白屈菜红碱（CHEL）是一种季苯并菲啶阳离子，在生理条件下会与GSH反应形成可逆加合物。在这里我们报道，当CHEL在极化犬肾细胞中组成性表达时，它可以强烈刺激Mrp2刺激GSH流出，从而导致细胞GSH耗竭。经上皮转运实验表明，Mrp2以1：1的化学计量比转运GSH和CHEL，很容易被GS-bimane（Mrp2的GS-X底物）抑制。此外，在存在GSH的情况下，CHEL可以阻止IC50约为100 microM的膜小泡对Mrp2介导的白三烯C4的摄取，但对S-甲基GSH或邻苯二甲酸则没有作用。因此，在CHEL存在下，抑制Mrp2需要GSH的巯基。我们的结果表明，CHEL通过形成可逆的GS-CHEL加合物来刺激GSH外排，该加合物由Mrp2转运并在细胞外解离。

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