Diminished drug transport and augmented radiation sensitivity caused by loss of RLIP76

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• 作者：Sharad S. Singhal ; Sushma Yadav ; Jyotsana Singhal ; Mukesh Sahu ; Archana Sehrawat ; Sanjay Awasthi
• 关键词：Ral-interacting protein ; Drug resistance ; Glutathione conjugate ; Transport ; Embryonic fibroblasts
• 刊名：FEBS Letters
• 出版年：2008
• 出版时间：15 October 2008
• 年：2008
• 卷：582
• 期：23-24
• 页码：3408-3414
• 全文大小：421 K

文摘

This study was undertaken to characterize the consequences of Ral-interacting protein (RLIP76)-loss with respect to drug resistance, transport, radiation resistance, and alternative transport mechanisms in mouse embryonic fibroblasts (MEFs). MEFs were derived from RLIP76^+/+, RLIP76^+/− and RLIP76^−/− mice. The transport of doxorubicin (DOX), colchicine (COL), leukotriene C₄ and dinitrophenyl S-glutathione (DNP-SG) was analyzed in inside-out vesicles (IOVs) prepared from MEFs. We used immuno-titration of transport activity to determine the contribution of RLIP76, MRP1, and p-glycoprotein (Pgp) towards total transport activity. Loss of RLIP76 alleles resulted in significant sensitization to radiation, DOX, cisplatin, and vinorelbine (VRL). In IOVs prepared from MEFs, we observed a stepwise loss of transport activity. Loss of RLIP76 confers sensitivity to xenobiotics and radiation due to the loss of a common transport mechanism for glutathione–electrophile conjugates and xenobiotics.