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

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. 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. The plasma membrane of mammalian cells has diverse functions, many of which are impaired by oxidative damage to its constituent lipids and proteins. The effects of such damage are seen in conditions ranging from natural ageing to type II diabetes, as well as specific diseases of the nervous and cardiovascular systems (1.Evans J.L. Maddux B.A. Goldfine I.D. The molecular basis for oxidative stress-induced insulin resistance.Antioxid. Redox Signal. 2005; 7: 1040-1052Crossref PubMed Scopus (446) Google Scholar, 2.Finkel T. Holbrook N.J. Oxidants, oxidative stress and the biology of ageing.Nature. 2000; 408: 239-247Crossref PubMed Scopus (7300) Google Scholar, 3.Molavi B. Mehta J.L. Oxidative stress in cardiovascular disease: molecular basis of its deleterious effects, its detection, and therapeutic considerations.Curr. Opin. Cardiol. 2004; 19: 488-493Crossref PubMed Scopus (127) Google Scholar, 4.Montine T.J. Neely M.D. Quinn J.F. Beal M.F. Markesbery W.R. Roberts L.J. Morrow J.D. Lipid peroxidation in aging brain and Alzheimer's disease.Free Radic. Biol. Med. 2002; 33: 620-626Crossref PubMed Scopus (380) Google Scholar). It is not surprising, therefore, that antioxidants such as vitamin E have attracted considerable attention as potential protective or palliative agents. In vitro, vitamin E has been widely demonstrated as having a free radical-scavenging antioxidant action (5.Kamal-Eldin A. Appelqvist L.A. The chemistry and antioxidant properties of tocopherols and tocotrienols.Lipids. 1996; 31: 671-701Crossref PubMed Scopus (1483) Google Scholar). However, its mechanism of action in vivo remains controversial (6.Azzi A. Molecular mechanism of alpha-tocopherol action.Free Radic. Biol. Med. 2007; 43: 16-21Crossref PubMed Scopus (331) Google Scholar, 7.Brigelius-Flohé R. Vitamin E: the shrew waiting to be tamed.Free Radic. Biol. Med. 2009; 46: 543-554Crossref PubMed Scopus (211) Google Scholar), as treatment with vitamin E has yielded negligible benefit against oxidative stress and in some instances has resulted in cytotoxic effects (8.Brigelius-Flohé R. Kelly F.J. Salonen J.T. Neuzil J. Zingg J.M. Azzi A. The European perspective on vitamin E: current knowledge and future research.Am. J. Clin. Nutr. 2002; 76: 703-716Crossref PubMed Scopus (508) Google Scholar, 9.Golbidi S. Ebadi S.A. Laher I. Antioxidants in the treatment of diabetes.Curr. Diabetes Rev. 2011; 7: 106-125Crossref PubMed Scopus (147) Google Scholar, 10.Robinson I. de Serna D.G. Gutierrez A. Schade D.S. Vitamin E in humans: an explanation of clinical trial failure.Endocr. Pract. 2006; 12: 576-582Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 11.Saremi A. Arora R. Vitamin E and cardiovascular disease.Am. J. Ther. 2010; 17: e56-e65Crossref PubMed Scopus (105) Google Scholar). In the present report, we demonstrate that vitamin E has the capability to modify the membrane dipole potential (MDP). We also show evidence that tocopherol-dependent changes of the MDP can lead to changes of the ligand binding capability of the multi-drug efflux pump, P-glycoprotein (P-gp). Such observations suggest, therefore, that it is worth considering that some of the reported effects of tocopherols may arise through such mechanisms [as outlined in (12.O'Shea P. Physical landscapes in biological membranes: physico-chemical terrains for spatio-temporal control of biomolecular interactions and behaviour.Philos. Trans. A Math. Phys. Eng. Sci. 2005; 363: 575-588Crossref PubMed Scopus (61) Google Scholar)] rather than resulting solely from antioxidant properties. α-Tocopherol is the form of vitamin E most preferentially absorbed by the human body (13.Hosomi A. Arita M. Sato Y. Kiyose C. Ueda T. Igarashi O. Arai H. Inoue K. Affinity for alpha-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs.FEBS Lett. 1997; 409: 105-108Crossref PubMed Scopus (521) Google Scholar), despite the β, γ, and δ isoforms and the tocotrienol counterparts, also exhibiting free radical-scavenging action in vitro (14.Yoshida Y. Niki E. Noguchi N. Comparative study on the action of tocopherols and tocotrienols as antioxidant: chemical and physical effects.Chem. Phys. Lipids. 2003; 123: 63-75Crossref PubMed Scopus (273) Google Scholar). This observation, along with other evidence, supports the argument that α-tocopherol must have significant nonantioxidant roles not shared by other antioxidants (6.Azzi A. Molecular mechanism of alpha-tocopherol action.Free Radic. Biol. Med. 2007; 43: 16-21Crossref PubMed Scopus (331) Google Scholar), prompting investigations to identify the nonantioxidant physiological effects of α-tocopherol. α-Tocopherol succinate has received attention as an analog of α-tocopherol that demonstrates no in vitro free radical-scavenging action (15.Neuzil J. Weber T. Gellert N. Weber C. Selective cancer cell killing by alpha-tocopheryl succinate.Br. J. Cancer. 2001; 84: 87-89Crossref PubMed Scopus (222) Google Scholar), but is reported to possess clinically relevant effects, such as improving the efficacy of chemotherapy when administered as a cotherapeutic agent (16.Prasad K.N. Kumar B. Yan X.D. Hanson A.J. Cole W.C. Alpha-tocopheryl succinate, the most effective form of vitamin E for adjuvant cancer treatment: a review.J. Am. Coll. Nutr. 2003; 22: 108-117Crossref PubMed Scopus (171) Google Scholar, 17.Ripoll E.A. Rama B.N. Webber M.M. Vitamin E enhances the chemotherapeutic effects of adriamycin on human prostatic carcinoma cells in vitro.J. Urol. 1986; 136: 529-531Crossref PubMed Google Scholar). This effect is likely to involve the multi-drug efflux pump, P-gp, but the underlying mechanism responsible is not well-understood. Both α-tocopherol and its succinate ester analog, the structures of which are shown in Fig. 1, are reported to have a number of effects on model biological membranes. These include: imparting a negative curvature stress (18.Bradford A. Atkinson J. Fuller N. Rand R.P. The effect of vitamin E on the structure of membrane lipid assemblies.J. Lipid Res. 2003; 44: 1940-1945Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar) and modifying the phase behavior of lipids; decreasing the enthalpy of the gel to liquid crystalline transition by influencing lipid organization (19.Massey J.B. Interfacial properties of phosphatidylcholine bilayers containing vitamin E Phys. Lipids. 2001; PubMed Scopus Google Scholar, the of alpha-tocopherol in membranes with its 2004; PubMed Scopus Google and phase as a of with specific lipids A. F.J. A study of the of alpha-tocopherol with of PubMed Scopus Google Scholar, F.J. alpha-tocopherol and with of 1996; PubMed Scopus Google Scholar). The present study the effect of α-tocopherol and α-tocopherol succinate on the which is a of changes in lipid organization and that of (12.O'Shea P. Physical landscapes in biological membranes: physico-chemical terrains for spatio-temporal control of biomolecular interactions and behaviour.Philos. Trans. A Math. Phys. Eng. Sci. 2005; 363: 575-588Crossref PubMed Scopus (61) Google Scholar, B. J. of with A and study of and in phosphatidylcholine PubMed Scopus Google Scholar, H. potential of lipid Phys. Lipids. PubMed Scopus Google Scholar, J. P. molecular the membrane and of a model J. Full Text Full Text PDF PubMed Scopus Google Scholar, of lipid structure on the dipole potential of phosphatidylcholine 1997; PubMed Scopus Google Scholar, K. J. Rand R.P. Fuller N. dipole and the ordering of membrane J. Full Text PDF PubMed Scopus Google Scholar, T. N. M.F. effect on the dipole potential of lipid J. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar), and influences the behavior of membrane J. P. molecular the membrane and of a model J. Full Text Full Text PDF PubMed Scopus Google Scholar, T. J. P. of the membrane dipole potential on the of saquinavir with membranes and plasma membrane of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, P. interactions cell membranes and the of membrane and Trans. 2003; 31: PubMed Google Scholar). We fluorescent in as of molecular interactions with membranes P. interactions cell membranes and the of membrane and Trans. 2003; 31: PubMed Google Scholar). The is an of the and the or of to the membrane The fluorescent probe, 1-(3-sulfonatopropyl)-4-[β[2-(di-n-octylamino)-6-naphthyl]vinyl] pyridinium the of the MDP and its use as an of molecular interactions is in (12.O'Shea P. Physical landscapes in biological membranes: physico-chemical terrains for spatio-temporal control of biomolecular interactions and behaviour.Philos. Trans. A Math. Phys. Eng. Sci. 2005; 363: 575-588Crossref PubMed Scopus (61) Google Scholar, J. P. molecular the membrane and of a model J. Full Text Full Text PDF PubMed Scopus Google Scholar, T. J. P. of the membrane dipole potential on the of saquinavir with membranes and plasma membrane of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, P. interactions cell membranes and the of membrane and Trans. 2003; 31: PubMed Google Scholar). The of these is that can be in the in model membrane systems as in cell membranes T. J. P. of the membrane dipole potential on the of saquinavir with membranes and plasma membrane of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google We use these to show that in cells α-tocopherol succinate and the dipole potential and influence the of the saquinavir with P-gp. succinate, and by phosphatidylcholine by Lipid by and from and from other also by the and with as in T. J. P. of the membrane dipole potential on the of saquinavir with membranes and plasma membrane of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). succinate, and in the and the by a of The resulting lipid with and and to in liquid to the of vesicles. the through with an to the of by a 1986; PubMed Scopus Google Scholar). This a of vesicles. and succinate, or by with in from for in with and and with The cell a to by with by a of cells with for as outlined by T. J. P. of the membrane dipole potential on the of saquinavir with membranes and plasma membrane of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). cells with to the of J. I. P. The of with on the cell J. 2001; PubMed Scopus Google Scholar). the from a of in by a of The resulting in a of of the of and in and to a in cells and for from cells in by to and cells in and to cholesterol from the plasma membrane of cells a from C. C. of the of cholesterol in in cell Signal. 2006; PubMed Scopus Google Scholar) reported to in the of most of the cholesterol from membrane with negligible effects on cell with or cells in by to in and for and in and to cell and to the cells with α-tocopherol succinate, or the and for the relevant to to the cells in a a with fluorescent with a from and cells. The of membrane to the dipole potential to in the dipole potential of of and the changes in the dipole potential on the of α-tocopherol succinate and with and cell membranes. of of and and an of a the of with to its to the of the resulting in a A of the dipole potential of of by the and and the of the The in the dipole potential of resulting from of by the of the a in the changes in the MDP on of α-tocopherol succinate, or saquinavir to or cell lipid or cells in the The of the of on of the and a and the in the dipole potential by the in the the the of the The effect of of and of the on the by of or not to or cell over a and resulting changes from on the of α-tocopherol succinate, or These to and and the model the an is the in the is the of α-tocopherol succinate, or saquinavir is the the affinity of the binding for the membrane or is the binding of the membrane or for the and the as an of The for the of α-tocopherol succinate with T-lymphocytes, with or cholesterol in a similar by and to the in with of α-tocopherol succinate The of the of with of α-tocopherol succinate to a of cells The the of the a in in α-tocopherol succinate the in the This for the effects of of and of the by the in on the of of over a and and The influence of α-tocopherol and α-tocopherol succinate on the MDP in a lipid membrane containing α-tocopherol or its analog α-tocopherol succinate lipid by of by a 1986; PubMed Scopus Google Scholar). The in the MDP to the of these of vitamin E by the in the of the fluorescent probe, (12.O'Shea P. Physical landscapes in biological membranes: physico-chemical terrains for spatio-temporal control of biomolecular interactions and behaviour.Philos. Trans. A Math. Phys. Eng. Sci. 2005; 363: 575-588Crossref PubMed Scopus (61) Google Scholar). for by the of in from that in the vesicles. α-Tocopherol induced a of a in shown are the for containing cholesterol and its which have previously been demonstrated to and the dipole T. N. M.F. effect on the dipole potential of lipid J. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, T. J. P. of the membrane dipole potential on the of saquinavir with membranes and plasma membrane of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the in dipole potential induced by the and α-tocopherol succinate in is shown in Fig. α-Tocopherol a in the dipole potential of similar in to that induced by but in the with on lipid membranes F.J. alpha-tocopherol and with of 1996; PubMed Scopus Google Scholar). α-Tocopherol succinate, the non-free radical-scavenging analog of to have a similar effect on The influence of and α-tocopherol succinate, the of the on the dipole potential of cell membranes by the cells to of Both decreased the dipole potential with the as seen in vesicles. an agent in is to as a ligand of the multi-drug efflux pump, P-gp Cole and by protein Lett. 2006; PubMed Scopus Google Scholar). These interactions can be in cell as lead to changes of the dipole potential T. J. P. of the membrane dipole potential on the of saquinavir with membranes and plasma membrane of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The binding of saquinavir to shown in Fig. a its with a in a similar to that in with cells T. J. P. of the membrane dipole potential on the of saquinavir with membranes and plasma membrane of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). of with α-tocopherol succinate reduced the affinity of saquinavir for P-gp, demonstrated by an in the for the which decreases the dipole also decreased the affinity of saquinavir for P-gp with on the influence of a in the dipole potential on P-gp T. J. P. of the membrane dipole potential on the of saquinavir with membranes and plasma membrane of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). α-tocopherol succinate, which decreases the MDP to a than demonstrated the effect on the affinity of saquinavir for P-gp. The influence of or α-tocopherol succinate treatment on the of the binding of saquinavir may an explanation for the the of influence on the dipole potential and P-gp activity. the of the binding the of in the is not treatment with α-tocopherol succinate, however, the is reduced This that α-tocopherol succinate is a significant effect on the of the binding mechanism that is not induced by and for the of saquinavir with and from of a binding model to the in Fig. for the of saquinavir with T-lymphocytes, or with α-tocopherol succinate or in a The and from of a binding model to the in Fig. for the of saquinavir with T-lymphocytes, or with α-tocopherol succinate or The mechanism underlying the of the is however, the of P-gp is to be membrane M. J. R. P-glycoprotein is in in cells and in brain Lett. 2000; PubMed Scopus Google Scholar, K. I. are in membrane in human cancer Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). The is to show a preference for the dipole potential with T. J. P. of the membrane dipole potential on the of saquinavir with membranes and plasma membrane of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, P. interactions cell membranes and the of membrane and Trans. 2003; 31: PubMed Google Scholar) to lipid and decreased T. N. M.F. effect on the dipole potential of lipid J. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. B. K. P. H. of in cell J. PubMed Scopus Google Scholar). The treatment of with to these via cholesterol depletion C. C. of the of cholesterol in in cell Signal. 2006; PubMed Scopus Google Scholar) decreased the affinity of saquinavir for P-gp the of P-gp is membrane The for the also reduced that may have an in the underlying mechanism of the the effect of and α-tocopherol succinate on the of the is similar on We that α-tocopherol succinate influences P-gp by decreasing the dipole potential of P-gp that is with membrane We as α-Tocopherol succinate in membrane it to the dipole the of α-tocopherol succinate with cells or with cholesterol to the of in the plasma membrane or with to microdomain The for α-tocopherol succinate binding to these from binding from of the in or dipole potential induced by the binding P. interactions cell membranes and the of membrane and Trans. 2003; 31: PubMed Google Scholar), with that for α-tocopherol succinate binding to cells treatment the affinity of α-tocopherol succinate for the membrane on treatment the effect on The affinity of α-tocopherol succinate for membranes in it has a preference these structures and is likely to the dipole potential with across the The present study demonstrates that the of α-tocopherol and its α-tocopherol succinate, with biological membranes to changes of the A of these interactions and effects in to of cholesterol is shown in Fig. α-tocopherol succinate is a non-free radical-scavenging analog of effect is and may be free radical-scavenging for α-tocopherol. membranes with α-tocopherol succinate to influence the of the most likely through effects on the multi-drug efflux pump, P-gp. This membrane is reported to be to in the dipole potential T. J. P. of the membrane dipole potential on the of saquinavir with membranes and plasma membrane of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) and its is and T. J. P. of the membrane dipole potential on the of saquinavir with membranes and plasma membrane of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, K. I. Lipid of and Phys. Lipids. 2009; PubMed Scopus Google Scholar, S. S. A. P-glycoprotein and some on or by Sci. 2006; PubMed Scopus Google Scholar) with membrane α-Tocopherol succinate is shown to have a affinity for membranes in these its within these evidence for the of succinate with membrane remains is by observations that the membrane of succinate influences the of protein J. E. J. I. Vitamin E of to lipid 2007; PubMed Scopus Google Scholar, Atkinson J. Vitamin antioxidant and Radic. Biol. Med. 2007; 43: PubMed Scopus Google Scholar). In the present the membrane interactions of succinate also shown to influence the of the with similar effect to microdomain disruption via membrane cholesterol We that the mechanism by which α-tocopherol succinate influences P-gp is via its effect to the dipole potential of membrane with which In of an form of cholesterol to in in membrane of cells with Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. S. de A. is impaired by vitamin E: a specific for alpha-tocopherol with on cell Biol. 2009; Full Text Full Text PDF PubMed Scopus (69) Google Scholar) and demonstrated to the dipole potential of the plasma also shown to influence the of saquinavir with P-gp. The in the to which α-tocopherol succinate and influence the dipole potential and P-gp are suggested to be to in within membranes in of with P-gp in The specific influence of on the microdomain of membranes and the resulting in dipole potential across the membrane are likely to be which with activity. The implications of α-tocopherol succinate of P-gp are The of many and be to the reduced of P-gp to from the In to the potential negative effects may α-tocopherol succinate treatment may the efficacy of therapeutic by In α-tocopherol succinate may also have a in multi-drug This is with P-gp which is to a of from and such as saquinavir J.M. of P-glycoprotein by succinate Res. PubMed Scopus Google Scholar, The of Rev. PubMed Scopus Google Scholar, M.M. I. of by the Rev. PubMed Scopus Google Scholar). of P-gp is in some cells M.M. T. in of Rev. Cancer. 2002; PubMed Scopus Google Scholar) and the in drug is with the of chemotherapy The of Rev. PubMed Scopus Google Scholar, M.M. I. of by the Rev. PubMed Scopus Google Scholar). α-tocopherol succinate treatment has been shown to the efficacy of some chemotherapeutic (16.Prasad K.N. Kumar B. Yan X.D. Hanson A.J. Cole W.C. Alpha-tocopheryl succinate, the most effective form of vitamin E for adjuvant cancer treatment: a review.J. Am. Coll. Nutr. 2003; 22: 108-117Crossref PubMed Scopus (171) Google Scholar, 17.Ripoll E.A. Rama B.N. Webber M.M. Vitamin E enhances the chemotherapeutic effects of adriamycin on human prostatic carcinoma cells in vitro.J. Urol. 1986; 136: 529-531Crossref PubMed Google Scholar) and effect be therefore, by a similar mechanism to that in present delivery across biological is a for the delivery of to The in brain drug 2005; PubMed Scopus Google Scholar). such as P-gp an in and by a of and of cells P-glycoprotein for drug 7: PubMed Scopus Google Scholar). P-gp is in biological the a in the Rev. PubMed Scopus Google Scholar), S. C. K. K. of P-glycoprotein on of and Sci. PubMed Scopus Google Scholar), S. J. B. P. Molecular evidence and of P-glycoprotein in human and and cell Sci. 2003; 44: PubMed Scopus (105) Google Scholar), and J. an determinant in 2003; PubMed Scopus Google Scholar). In of protein has also been to a in the of multi-drug cancer R. B. and and 2005; PubMed Google Scholar). of P-gp are to drug delivery across biological C. O. of the brain by of Res. 2003; Google Scholar, C. C. S. S. A. A. of of through vitamin E a in J. PubMed Scopus Google Scholar), of administered of by of the P-glycoprotein Res. 2003; PubMed Scopus Google Scholar), and multi-drug T. M. S. of as P-glycoprotein in cancer Sci. 2009; 12: PubMed Google Scholar). these has been considerable in the of P-gp P-glycoprotein for drug 7: PubMed Scopus Google Scholar). α-tocopherol succinate is reported to of therapeutic and through P-gp J.M. of P-glycoprotein by succinate Res. PubMed Scopus Google Scholar, J. in the use of as drug delivery Res. 2006; PubMed Scopus Google Scholar). This α-tocopherol succinate is likely to influence the dipole potential in a similar to α-tocopherol and its succinate ester and modulate P-gp via the The dipole potential is a determinant of the of membrane in to the P-gp in the present and many have been as present in membrane observations may to a of and cell through its in membrane S. C. S. de A. is impaired by vitamin E: a specific for alpha-tocopherol with on cell Biol. 2009; Full Text Full Text PDF PubMed Scopus (69) Google Scholar), may influence the of via the mechanism we for α-tocopherol the of mechanism may to the diverse and which have been to vitamin E. In the present study demonstrates that α-tocopherol and α-tocopherol succinate modulate the dipole potential of and cell membranes. This effect may an explanation of the diverse physiological of vitamin E. In effect the basis of a mechanism for the of P-gp by α-tocopherol the potential for the of these in multi-drug and in drug delivery across biological barriers. The are to the as some to the have to the of the 1-(3-sulfonatopropyl)-4-[β[2-(di-n-octylamino)-6-naphthyl]vinyl] pyridinium membrane dipole potential phosphatidylcholine P-glycoprotein