Structural changes in oxidised low-density lipoproteins and of the effect of the anti-atherosclerotic drug probucol observed by synchrotron X-ray and neutron solution scattering.
The atherosclerotic properties of low-density lipoproteins (LDL) are thought to be strongly enhanced by oxidation. The lipid-lowering drug probucol reduces the susceptibility of LDL to oxidation. Synchrotron X-ray and high-flux neutron solution scattering curves were used to characterise the structural properties of human LDL, before and after modification by oxidation with Cu2+ and the addition of probucol, in order to evaluate these techniques. Analyses based on Guinier plots, simple two-shell spherical modelling, and the use of cubic splines and indirect transformation show that a 20-h incubation with Cu2+ ions (but not 6 h) causes some of the LDL to associate to form larger aggregated particles. Gel electrophoresis on Cu2+ -oxidised LDL shows a concomitant degradation of the apolipoprotein B-100 as well as the formation of high molecular mass forms. These experiments indicate that the apoprotein B-100 structure has been significantly disrupted by oxidation. The addition of probucol to LDL causes an increase in the polydispersity of LDL, as evidenced by small changes in the Guinier curves and some weakening of the minima in the X-ray scattering curves. No changes in the quasispherical shape of LDL are observed and gel electrophoresis indicates no changes. It is possible that probucol may exert its effect by increasing the range of sizes of LDL and that the lipid-lowering effect of probucol in vivo might be caused by the preferential catabolism of the higher molecular mass forms of LDL thus created.
Department of Biochemistry and Chemistry, Royal Free Hospital School of Medicine, London England.
M F
MF
Bellamy
A S
AS
Nealis
J W
JW
Aitken
K R
KR
Bruckdorfer
S J
SJ
Perkins
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood; D001161:Arteriosclerosis / Q000097:blood / Q000188:drug therapy; D003300:Copper / Q000494:pharmacology; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood*; D046911:Macromolecular Substances; D009502:Neutrons; D010084:Oxidation-Reduction; D010315:Particle Accelerators; D010636:Phenols / Q000494:pharmacology*; D011341:Probucol / Q000494:pharmacology* / Q000627:therapeutic use; D012542:Scattering, Radiation; D014965:X-Rays
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; D046911:Macromolecular Substances; D010636:Phenols; D003300:Copper; D011341:Probucol