alpha-Tocopherols modify the membrane dipole potential leading to modulation of ligand binding by P-glycoprotein

Davis, Sterenn and Davis, Benjamin M. and Richens, Joanna L. and Vere, Kelly-Ann and Petrov, Peter G. and Winlove, C. Peter and O'Shea, Paul (2015) alpha-Tocopherols modify the membrane dipole potential leading to modulation of ligand binding by P-glycoprotein. JOURNAL OF LIPID RESEARCH, 56 (8). pp. 1543-1550. ISSN 0022-2275

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Abstract

α-Tocopherol (vitamin E) has attracted considerable attention as a potential protective or palliative agent. In vitro, its free radical-scavenging antioxidant action has been widely demonstrated. In vivo, however, vitamin E treatment exhibits negligible benefits against oxidative stress. α-Tocopherol influences lipid ordering within biological membranes and its derivatives have been suggested to inhibit the multi-drug efflux pump, P-glycoprotein (P-gp). This study employs the fluorescent membrane probe, 1-(3-sulfonatopropyl)-4-[β[2-(di-n-octylamino)-6-naphthyl]vinyl] pyridinium betaine, to investigate whether these effects are connected via influences on the membrane dipole potential (MDP), an intrinsic property of biological membranes previously demonstrated to modulate P-gp activity. α-Tocopherol and its non-free radical-scavenging succinate analog induced similar decreases in the MDP of phosphatidylcholine vesicles. α-Tocopherol succinate also reduced the MDP of T-lymphocytes, subsequently decreasing the binding affinity of saquinavir for P-gp. Additionally, α-tocopherol succinate demonstrated a preference for cholesterol-treated (membrane microdomain enriched) cells over membrane cholesterol-depleted cells. Microdomain disruption via cholesterol depletion decreased saquinavir’s affinity for P-gp, potentially implicating these structures in the influence of α-tocopherol succinate on P-gp. This study provides evidence of a microdomain dipole potential-dependent mechanism by which α-tocopherol analogs influence P-gp activity. These findings have implications for the use of α-tocopherol derivatives for drug delivery across biological barriers.

Item Type:
Journal Article
Journal or Publication Title:
JOURNAL OF LIPID RESEARCH
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1310
Subjects:
ID Code:
126042
Deposited By:
Deposited On:
22 Jun 2018 08:42
Refereed?:
Yes
Published?:
Published
Last Modified:
18 Sep 2020 04:17