Physiological and pharmacological significance of glutathione-conjugate transport.
Transport of the glutathione conjugates (GS-E) of electrophilic compounds generated during biotransformation of drugs and environmental pollutants is central to the mechanisms of defense against oxidative/electrophilic stress. In recent years emphasis has been placed on ATP-binding cassette (ABC) transport proteins in the transport of GS-E and their involvement in the detoxification mechanisms, including drug resistance. Recent studies, however, suggested that the majority of GS-E transport in human and rodent cells is mediated by a non-ABC, multifunctional stress-response protein, RLIP76 or RalBP1 (ral-binding GTPase activating protein 1), which also functions as an effector in the Ral-Ras-Rho signaling pathway. In this review, after briefly describing the major discoveries in the field of glutathione (GSH)-conjugate transport, recent findings are presented on the role of RLIP76 in ATP-dependent transport of GS-E, and the relevance of this transport process to the mechanisms of toxicity of xenobiotics, radiation, and endogenous electrophilic toxicants is described. Furthermore, recent studies suggesting a link between RLIP76 mediated GS-E transport and cell cycle signaling are presented.
Awasthi
Yogesh C
YC
Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA. yawasthi@hsc.unt.edu
Chaudhary
Pankaj
P
Vatsyayan
Rit
R
Sharma
Abha
A
Awasthi
Sanjay
S
Sharma
Rajendra
R
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D004351:Drug Resistance; D019008:Drug Resistance, Neoplasm; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism*; D006801:Humans; D016877:Oxidants / Q000633:toxicity; D011836:Radiation Tolerance; D015398:Signal Transduction; D015262:Xenobiotics / Q000633:toxicity
D018528:ATP-Binding Cassette Transporters; D020690:GTPase-Activating Proteins; D016877:Oxidants; C095637:RALBP1 protein, human; D015262:Xenobiotics; C030190:S-(2,4-dinitrophenyl)glutathione; D005978:Glutathione