Antioxidants inhibit low density lipoprotein oxidation less at lysosomal pH: a possible explanation as to why the clinical trials of antioxidants might have failed

Oxidised low density lipoprotein (LDL) was considered to be important in the pathogenesis of atherosclerosis, but the large clinical trials of antioxidants, including the first one using probucol (the PQRST Trial), failed to show benefit and have cast doubt on the importance of oxidised LDL. We have shown previously that LDL oxidation can be catalysed by iron in the lysosomes of macrophages. The aim of this study was therefore to investigate the effectiveness of antioxidants in preventing LDL oxidation at lysosomal pH and also establish the possible mechanism of oxidation. Probucol did not effectively inhibit the oxidation of LDL at lysosomal pH, as measured by conjugated dienes or oxidised cholesteryl esters or tryptophan residues in isolated LDL or by ceroid formation in the lysosomes of macrophage-like cells, in marked contrast to its highly effective inhibition of LDL oxidation at pH 7.4. LDL oxidation at lysosomal pH was inhibited very effectively for long periods by N,N'-diphenyl-1,4-phenylenediamine, which is more hydrophobic than probucol and has been shown by others to inhibit atherosclerosis in rabbits, and by cysteamine, which is a hydrophilic antioxidant that accumulates in lysosomes. Iron-induced LDL oxidation might be due to the formation of the superoxide radical, which protonates at lysosomal pH to form the much more reactive, hydrophobic hydroperoxyl radical, which can enter LDL and reach its core. Probucol resides mainly in the surface monolayer of LDL and would not effectively scavenge hydroperoxyl radicals in the core of LDL. This might explain why probucol failed to protect against atherosclerosis in various clinical trials. The oxidised LDL hypothesis of atherosclerosis now needs to be re-evaluated using different and more effective antioxidants that protect against the lysosomal oxidation of LDL

Effect of cyclodextrin encapsulation on the photocyclization of diphenylamine: Cavity imposed restriction on the reaction rate

The kinetics of the photocyclization of diphenylamine (DPA) to carbazole (CAZL) has been studied fluorometrically in air-equilibrated aqueous solution as well as in constrained microheterogeneous media provided by [alpha]-, [beta]-, and [gamma]- cyclodextrins (CDs). It is observed that the fluorophore is embedded within the CD cavities without any alteration of the overall reaction quantum yield in the different environments. However, the rate of the photoreaction is modified remarkably within the CD environments. A restriction on the intramolecular rotation of the phenyl planes of DPA, imposed by the steric rigidity within the CD cavities, has been ascribed to be responsible for the suppression of the reaction rates within the CD environments. A semi-empirical (AM1) calculation gives the molecular dimension of the substrate and corroborates the proposition from a consideration of the cavity size of the different cyclodextrins.http://www.sciencedirect.com/science/article/B6TGR-44WJT2F-D/1/fbeee114a055a066bec9406d2538f43

CONCERTED ELECTRON AND PROTON MOVEMENT IN QUENCHING OF TRIPLET C-60 AND TETRACENE FLUORESCENCE BY HYDROGEN-BONDED PHENOL-BASE PAIRS

The quenching of triplet Cm and tetracene fluorescence by phenols is strongly enhanced by added pyridines. Evidence that this is due to quenching by hydrogen-bonded phenol-base pairs is given by the close agreement between equilibrium constants for hydrogen-bond formation derived from kinetic measurements and from independent spectroscopic data. The effect is attributed to a trimolecular transition state in which electron transfer from the phenol to the excited molecule is concerted with proton movement from the incipient strongly acidic phenol cation radical to the hydrogen-bonded base

Cage escape and spin rephasing of triplet ion-radical pairs: temperature-viscosity and magnetic field effects in photoreduction of fluorenone by dabco

Weak magnetic fields are found to increase the bulk ion-radical yield from a triplet radical pair, in temperature-viscosity region where cage recombination occurs. The results are consistent with Noyes' theory of geminate reactions and a hyperfine coupling mechanism for spin inversion leading to quenching