TY - JOUR
T1 - Structure-activity analysis of flavonoids
T2 - Direct and indirect antioxidant, and antiinflammatory potencies and toxicities
AU - Tsuji, Petra A.
AU - Stephenson, Katherine K.
AU - Wade, Kristina L.
AU - Liu, Hua
AU - Fahey, Jed W.
N1 - Funding Information:
The authors wish to thank the Lewis B. and Dorothy Cull-man Foundation, the Cancer Prevention Fellowship Program of the National Cancer Institute, and National Institutes of Health Grant R01 CA093780 for funding, and Paul Talalay and Al-bena Dinkova-Kostova for stimulating discussions and editorial insight.
PY - 2013
Y1 - 2013
N2 - Flavonoids are secondary plant products that are well represented in healthy diets because of ingestion of fruit, vegetables, herbs, and teas. Increased consumption is correlated with decreased risks of cardiovascular disease, cancer, and other chronic diseases. Certain flavonoids confer direct antioxidant protection to cells, others induce enzymes that protect cells against oxidative and other insults ("indirect antioxidants"), and others appear to be protective by both mechanisms. Hydroxylated flavones manifest substantial direct antioxidant activity but do not effectively induce cytoprotective enzymes. Methoxylated flavones that potently induce cytoprotective enzymes were evaluated to elucidate the structural prerequisites for effective chemoprotective agents: protecting healthy cells with minimal collateral toxicity. Flavones and flavanones methoxylated at the 5-position of the A-ring were among the most potent inducers of the cytoprotective NAD(P)H:quinone-oxidoreductase 1 (NQO1) in 3 different cell lines. Other flavones were equally potent inducers, but more toxic. Flavanones contain no Michael reaction center, yet some are potent inducers of NQO1, have low cytotoxicity, and inhibit LPS-stimulated iNOS activity, which suggests a redox mechanism of action rather than the Keap1/Nrf2/ARE mechanism by which so many of the classic inducers operate. Evaluation in vivo will reveal whether differential protective advantages support their possible evaluation in a cancer prevention setting.
AB - Flavonoids are secondary plant products that are well represented in healthy diets because of ingestion of fruit, vegetables, herbs, and teas. Increased consumption is correlated with decreased risks of cardiovascular disease, cancer, and other chronic diseases. Certain flavonoids confer direct antioxidant protection to cells, others induce enzymes that protect cells against oxidative and other insults ("indirect antioxidants"), and others appear to be protective by both mechanisms. Hydroxylated flavones manifest substantial direct antioxidant activity but do not effectively induce cytoprotective enzymes. Methoxylated flavones that potently induce cytoprotective enzymes were evaluated to elucidate the structural prerequisites for effective chemoprotective agents: protecting healthy cells with minimal collateral toxicity. Flavones and flavanones methoxylated at the 5-position of the A-ring were among the most potent inducers of the cytoprotective NAD(P)H:quinone-oxidoreductase 1 (NQO1) in 3 different cell lines. Other flavones were equally potent inducers, but more toxic. Flavanones contain no Michael reaction center, yet some are potent inducers of NQO1, have low cytotoxicity, and inhibit LPS-stimulated iNOS activity, which suggests a redox mechanism of action rather than the Keap1/Nrf2/ARE mechanism by which so many of the classic inducers operate. Evaluation in vivo will reveal whether differential protective advantages support their possible evaluation in a cancer prevention setting.
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U2 - 10.1080/01635581.2013.809127
DO - 10.1080/01635581.2013.809127
M3 - Article
C2 - 24087992
AN - SCOPUS:84888347424
SN - 0163-5581
VL - 65
SP - 1014
EP - 1025
JO - Nutrition and Cancer
JF - Nutrition and Cancer
IS - 7
ER -