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J. Biol. Chem., Vol. 276, Issue 25, 23197-23206, June 22, 2001

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Glutathione-dependent Binding of a Photoaffinity Analog of Agosterol A to the C-terminal Half of Human Multidrug Resistance Protein^*

Xiao-Qin Ren^§, Tatsuhiko Furukawa, Shunji Aoki^¶, Tatsuo Nakajima^¶, Tomoyuki Sumizawa, Misako Haraguchi, Zhe-Sheng Chen, Motomasa Kobayashi^¶, and Shin-ichi Akiyama

From the  Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima 890-8520 and the ^¶ Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871, Japan

MRP1 is a 190-kDa membrane glycoprotein that confers multidrug resistance (MDR) to tumor cells. MRP1 is characterized by an N-terminal transmembrane domain (TMD₀), which is connected to a P-glycoprotein-like core region (MRP) by a cytoplasmic linker domain zero (L₀). It has been demonstrated that GSH plays an important role in MRP1-mediated MDR. However, the mechanism by which GSH mediates MDR and the precise roles of TMD₀ and L₀ are not known. We synthesized [¹²⁵I]11-azidophenyl agosterol A ([¹²⁵I]azidoAG-A), a photoaffinity analog of the MDR-reversing agent, agosterol A (AG-A), to photolabel MRP1, and found that the analog photolabeled the C-proximal molecule of MRP1 (C_932-1531) in a manner that was GSH-dependent. The photolabeling was inhibited by anticancer agents, reversing agents and leukotriene C₄. Based on photolabeling studies in the presence and absence of GSH using membrane vesicles expressing various truncated, co-expressed, and mutated MRP1s, we found that L₀ is the site on MRP1 that interacts with GSH. This study demonstrated that GSH is required for the binding of an unconjugated agent to MRP1 and suggested that GSH interacts with L₀ of MRP1. The photoanalog of AG-A will be useful for identifying the drug binding site within MRP1, and the role of GSH in transporting substrates by MRP1.

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