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Diminished drug transport and augmented radiation sensitivity caused by loss of RLIP76
Author(s) -
Singhal Sharad S.,
Yadav Sushma,
Singhal Jyotsana,
Sahu Mukesh,
Sehrawat Archana,
Awasthi Sanjay
Publication year - 2008
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2008.09.001
Subject(s) - drug , sensitivity (control systems) , radiation sensitivity , chemistry , medicine , pharmacology , irradiation , physics , nuclear physics , electronic engineering , engineering
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 C 4 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.