The effects of defatted safflower seed extract and its phenolic constituents, serotonin derivatives, on
atherosclerosis were studied. Ethanol-ethyl acetate extract of safflower seeds (SSE) inhibited lowdensity
lipoprotein (LDL) oxidation induced in vitro by an azo-containing free-radical initiator V70 or
copper ions. Two serotonin derivatives [N-(p-coumaroyl)serotonin, CS; N-feruloylserotonin, FS] and
their glucosides were identified as the major phenolic constituents of the extract. The study with
chemically synthesized materials revealed that a majority of the antioxidative activity of SSE was
attributable to the aglycones of these two serotonin derivatives. Orally administered CS and FS
suppressed CuSO4-induced plasma oxidation ex vivo. Long-term (15 week) dietary supplementation
of SSE (1.0 wt %/wt) and synthetic serotonin derivatives (0.2-0.4%) significantly reduced the
atherosclerotic lesion area in the aortic sinus of apolipoprotein E-deficient mice (29.2-79.7%
reduction). The plasma level of both lipid peroxides and anti-oxidized LDL autoantibody titers
decreased concomitantly with the reduction of lesion formation. Serotonin derivatives were detected
as both intact and conjugated metabolites in the plasma of C57BL/6J mice fed on 1.0% SSE diet.
These findings demonstrate that serotonin derivatives of SSE are absorbed into circulation and
attenuate atherosclerotic lesion development possibly because of the inhibition of oxidized LDL
formation through their strong antioxidative activity.