Ascorbate and phenolic antioxidant interactions in prevention of liposomal oxidation.
Efficient prevention of membrane lipid peroxidation by vitamin E (alpha-tocopherol) may involve its regeneration by vitamin C (ascorbate). Conceivably, the efficacy of antioxidants designed as therapeutic agents could be enhanced if a similar regeneration were favorable; thus, a model membrane system was developed which allowed assessment of interaction of phenolic antioxidants with ascorbate and ascorbyl-6-palmitate. Ascorbate alone (50-200 microM) potentiated oxidation of soybean phosphatidylcholine liposomes by Fe2+/histidine-Fe3+, an effect which was temporally related to reduction of Fe3+ generated during oxidation. Addition of 200 microM ascorbate to alpha-tocopherol-containing liposomes (0.1 mol%) resulted in marked, synergistic protection. Accordingly, in the presence but not absence of ascorbate, alpha-tocopherol levels were maintained relatively constant during Fe2+/histidine-Fe3+ exposure. Probucol (4,4'-[(1-methylethylidine)bis(thio)]bis[2,6-bis(1,1- dimethylethyl)]phenol), an antioxidant which prevents oxidation of low density lipoproteins, and its analogues MDL 27,968 (4,4'-[(1-methylethylidene)bis(thio)]bis[2,6- dimethyl]phenol) and MDL 28,881 (2,6-bis(1,1-dimethylethyl)-4-[(3,7,11- trimethyldodecyl)thio]phenol) prevented oxidation but exhibited no synergy with ascorbate. Ascorbyl-6-palmitate itself was an effective antioxidant but did not interact synergistically with any of the phenolic antioxidants. Differential scanning calorimetry revealed significant differences among the antioxidants in their effect on the liquid-crystalline phase transition of dipalmitoyl phosphatidylcholine (DPPC) liposomes. Both alpha-tocopherol and MDL 27,968 significantly reduced the phase transition temperature and the enthalpy of the transition. MDL 28,881 had no effect while probucol was intermediate. The potential for ascorbate or its analogues to interact with phenolic antioxidants to provide a more effective antioxidant system appears to be dictated by structural features and by the location of the antioxidants in the membrane.
Thomas
C E
CE
Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215.
McLean
L R
LR
Parker
R A
RA
Ohlweiler
D F
DF
D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D004357:Drug Synergism; D015227:Lipid Peroxidation / Q000187:drug effects; D008081:Liposomes / Q000737:chemistry*; D010084:Oxidation-Reduction; D010636:Phenols / Q000494:pharmacology*; D010713:Phosphatidylcholines / Q000737:chemistry; D011341:Probucol / Q000031:analogs & derivatives / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D008081:Liposomes; D010636:Phenols; D010713:Phosphatidylcholines; D013440:Sulfides; D014810:Vitamin E; C078481:2,6-bis(1,1-dimethylethyl)-4-((3,7,11-trimethyldodecyl)thio)phenol; C078480:MDL 27968; D011341:Probucol; D001205:Ascorbic Acid; C031226:6-O-palmitoylascorbic acid