Flavonoids: biochemical effects and therapeutic applications

Low density lipoproteins (LDL) can be oxidatively modified in vitro by macrophages and certain other cell types so that macrophages will take them up much faster. This process may be important in the formation of cholesterol-laden foam cells derived from macrophages in atherosclerotic lesions. In this study, we have shown that certain flavonoids, plant constituents found in the diet, are potent inhibitors of the modification of 125I-labelled LDL by macrophages, with IC50 values in the micromolar range (e.g. morin and fisetin 1 microM; quercetin and gossypetin 2 microM). The potencies of individual flavonoids in inhibiting LDL modification did not correlate with their previously determined potencies as inhibitors of 5-lipoxygenase and cyclo-oxygenase. The modification of LDL by macrophages exhibits a lag period of about 4-6 hr before enhanced uptake is detected. During this time, there is a rapid depletion in its content of alpha-tocopherol (an endogenous antioxidant found in lipoproteins) followed by a large increase in the level of hydroperoxides. The flavonoids conserved the alpha-tocopherol content of LDL and delayed the onset of detectable lipid peroxidation. Flavonoids also inhibited the cell-free oxidation of LDL mediated by CuSO4. These findings raise the possibility that flavonoids may protect LDL against oxidation in atherosclerotic lesions and may therefore be natural anti-atherosclerotic components of the diet, although this will depend to a large extent on their pharmacokinetics.

The interactions of phytoestrogens with estrogen receptors were studied in the human breast cancer cell line, MCF-7. The compounds tested were coumestrol, genistein, and formononetin and the mycotoxins, zearalenone and its reduced derivative, zearalenol. All but formononetin compete for binding of [3H]-estradiol to unfilled cytoplasmic estrogen receptor or unfilled nuclear estrogen receptor sites. Relative binding affinities are zearalenol HMP (high melting point isomer) greater than zearalenol LMP (low melting point isomer) greater than zearalenone = coumestrol greater than genistein greater than formononetin. Dissociation constants estimated from competition curves show that binding affinities are high. In contrast to estradiol, phytoestrogens bind only weakly to sex steroid-binding globulin; they also do not bind to corticosteroid-binding globulin. These compounds translocate the cytoplasmic estrogen receptor and bind to unfilled nuclear estrogen receptors in whole cells. Bound nuclear receptors are then processed in a manner similar to estradiol in a step which rapidly decreases total cellular estrogen receptors. The phytoestrogens are also biologically active; they can markedly enhance tumor cell proliferation. In sum, phytoestrogens interact with the estrogen receptors of human breast cancer cells in culture and, therefore, may affect estrogen-mediated events in these cells.