Molecular Basis of the Anti-Inflammatory Properties of Isoflavones
S. Barnes, T. D'Alessandro, J. Prasain, R. Moore II, M.
Kirk, N.P. Botting, R.P. Patel, V.M. Darley-Usmar
Department of Pharmacology & Toxicology
Room 602 Kaul Human Genetics Bdg
University of Alabama at Birmingham
720 20th St South
Birmingham, AL 35294
Isoflavones are members of the polyphenol family and are present in a
limited number of foods, principally soy-derived products. Their
consumption is associated with a lowered incidence of chronic
diseases such as atherosclerosis, cancer, cognitive decline and
osteoporosis. In many of these diseases, inflammation is an important
associated event. Polyphenols have long been assigned antioxidant and
antiinflammatory properties. However, there is a discordance between
their in vitro properties and their effects in vivo - the
concentrations needed in vitro far exceed the amounts present in the
blood. Since inflammation is a localized event around inflammatory
cells, we have examined the hypothesis that circulating isoflavones
alter the chemistry of that local environment and in doing so are
converted to new pharmacophores. Isoflavones contain two aromatic
rings both of which are analogous to the phenolic tyrosine residues
on proteins. They are converted to relatively stable free radicals
and can in turn react with other antioxidants such as vitamin C,
thereby increasing their antioxidant potency. In models of
inflammation, protein tyrosines in the vicinity of the inflammatory
cells are chlorinated (by HOCl generated by neutrophils) and nitrated
(by peroxynitrite generated by several inflammatory cell types). The
addition of HOCl and peroxynitrite to isoflavones leads to rapid
chlorination and nitration. Activation of neutrophils by phorbol
esters results in rapid chlorination of isoflavones. In a rat
lipopolysaccharide model of cholestasis, extensive nitration of
genistein is observed in the lung. Chlorinated daidzein and genistein
are more potent antioxidants in models of LDL oxidation. However,
they have 1-2 orders of magnitude lower effects on estrogen
receptor-dependent gene expression than their parent compounds. In
summary, a rationale for the larger biological effects of isoflavones
than can be detected in vitro was developed - this may arise from (1)
synergistic interaction with other antioxidants, (2) conversion at
local sites of inflammation to stronger antioxidants, and (3)
formation of weaker estrogenic metabolites. These events may each
have important roles in the prevention of aging.
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