The effects of alpha-tocopherol on the properties of model high-density lip
oproteins (HDLs), composed of human apolipoprotein A-l and dimyristoylphosp
hatidylcholine, were investigated by physicochemical methods. The intrinsic
fluorescence of alpha-tocopherol and its effects on the polarization of fl
uorescence of 1,6-diphenyl-1,3,5-hexatriene, which probes the hydrocarbon r
egion of the lipids, and 4-heptadecyl-7-hydroxycoumarin, which is a probe o
f lipid surfaces, suggest that alpha-tocopherol is located at the lipid-wat
er interface. Relative to cholesterol, alpha-tocopherol in lipid surfaces i
s virtually inert physicochemically. Incorporation of alpha-tocopherol into
HDLs induces only a modest increase in particle size, no change in the tra
nsition temperature, and little change in lipid polarity and lipid-lipid in
teractions. Moreover, alpha-tocopherol has only a negligible effect on the
kinetic parameters of the lipophilic enzyme lecithin:cholesterol acyltransf
erase, which binds to phosphatidylcholine surfaces and forms cholesteryl es
ters. However, alpha-tocopherol has a dramatic inhibitory effect on the rat
e of association of apolipoprotein A-l with dimyristoylphosphatidylcholine,
a process that occurs through the insertion of the protein into preformed
defects in the lipid surface. It is proposed that alpha-tocopherol inhibits
the rate of association of apolipoprotein A-I with dimyristoylphosphatidyl
choline by inserting into defects within the lipid surface, thereby reducin
g the size and/or number of sites for insertion of apolipoprotein A-l.