MRP1 mutated in the L0 region transports SN-38 but not leukotriene C4 or estradiol-17 (beta-D-glucuronate).
MRP1 mutated in the L0 region transports SN-38 but not leukotriene C4 or estradiol-17 (beta-D-glucuronate).
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DOI：
10.1016/j.bcp.2005.06.025
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发表时间：
2005-10
影响因子：
5.8
通讯作者：
T. Noguchi;X. Ren;S. Aoki;Yoshinobu Igarashi;Xiao-Fang Che;Y. Nakajima;H. Takahashi;Ryoichi Mitsuo;K. Tsujikawa;T. Sumizawa;M. Haraguchi;Motomasa Kobayashi;S. Goto;M. Kanehisa;T. Aikou;S. Akiyama;T. Furukawa
中科院分区：
文献类型：
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作者：
T. Noguchi;X. Ren;S. Aoki;Yoshinobu Igarashi;Xiao-Fang Che;Y. Nakajima;H. Takahashi;Ryoichi Mitsuo;K. Tsujikawa;T. Sumizawa;M. Haraguchi;Motomasa Kobayashi;S. Goto;M. Kanehisa;T. Aikou;S. Akiyama;T. Furukawa
多药耐药蛋白1 （MRP1）是一种atp结合盒转运蛋白，可对肿瘤细胞产生多药耐药。已经积累了许多令人信服的证据，表明MRP1以gsh依赖的方式运输大多数物质。另一方面，一些报道表明MRP1可以独立于谷胱甘肽转运一些底物；然而，gsh非依赖性转运活性的重要性尚未得到很好的确定，gsh依赖性转运和MRP1非依赖性转运之间的机制差异尚不清楚。我们之前已经证明MRP1的l0区域的氨基酸w261和k267对于MRP1的白三烯C4（LTC4）运输活性和MRP1的gsh依赖性光标记与azidoyl agosterl - a （azidoAG-A）很重要。在本文中，我们进一步测试了MRP1中W222L、W223L和R230A突变（称为dmL0MRP1）对MRP1转运活性的影响。SN-38是CPT-11的活性代谢形式，是最有前途的抗癌药物之一。由表达dmL0MRP1的细胞制备的膜泡可以运输SN-38，但不能运输ltc4或雌二醇-17 （β-d-葡萄糖酸盐），并且不能用azidoAG-A进行光标记。这些数据表明SN-38的转运机制不同于gsh依赖的转运机制。了解MRP1不依赖于gsh的转运机制，并鉴定通过该机制转运的药物，对于对抗MRP1介导的耐药至关重要。我们对MRP1以gsh依赖性或非依赖性方式运输的化合物进行了两两比较。这些数据表明，有可能预测由MRP1以不依赖于gsh的方式运输的化合物。
Multidrug resistance protein 1 (MRP1) is an ATP-binding cassette transporter that confers multidrug resistance on tumor cells. Much convincing evidence has accumulated that MRP1 transports most substances in a GSH-dependent manner. On the other hand, several reports have revealed that MRP1 can transport some substrates independently of GSH; however, the importance of GSH-independent transport activity is not well established and the mechanistic differences between GSH-dependent and -independent transport by MRP1 are unclear. We previously demonstrated that the amino acids W261and K267in the L0region of MRP1 were important for leukotriene C4(LTC4) transport activity of MRP1 and for GSH-dependent photolabeling of MRP1 with azidophenyl agosterol-A (azidoAG-A). In this paper, we further tested the effect of W222L, W223L and R230A mutations in MRP1, designated dmL0MRP1, on MRP1 transport activity. SN-38 is an active metabolic form of CPT-11 that is one of the most promising anti-cancer drugs. Membrane vesicles prepared from cells expressing dmL0MRP1 could transport SN-38, but not LTC4or estradiol-17 (β-d-glucuronate), and could not be photolabeled with azidoAG-A. These data suggested that SN-38 was transported by a different mechanism than that of GSH-dependent transport. Understanding the GSH-independent transport mechanism of MRP1, and identification of drugs that are transported by this mechanism, will be critical for combating MRP1-mediated drug resistance. We performed a pairwise comparison of compounds that are transported by MRP1 in a GSH-dependent or -independent manner. These data indicated that it may be possible to predict compounds that are transported by MRP1 in a GSH-independent manner.