The reaction of flavanols with nitrous acid protects against N-nitrosamine formation and leads to the formation of nitroso derivatives which inhibit cancer cell growth.
Studies have suggested that diets rich in polyphenols such as flavonoids may lead to a reduced risk of gastrointestinal cancers. We demonstrate the ability of monomeric and dimeric flavanols to scavenge reactive nitrogen species derived from nitrous acid. Both epicatechin and dimer B2 (epicatechin dimer) inhibited nitrous acid-induced formation of 3-nitrotyrosine and the formation of the carcinogenic N-nitrosamine, N-nitrosodimethylamine. The reaction of monomeric and dimeric epicatechin with nitrous acid led to the formation of mono- and di-nitroso flavanols, whereas the reaction with hesperetin resulted primarily in the formation of nitrated products. Although, epicatechin was transferred across the jejunum of the small intestine yielding metabolites, its nitroso form was not absorbed. Dimer B2 but not epicatechin monomer inhibited the proliferation of, and triggered apoptosis in, Caco-2 cells. The latter was accompanied by caspase-3 activation and reductions in Akt phosphorylation, suggesting activation of apoptosis via inhibition of prosurvival signaling. Furthermore, the dinitroso derivative of dimer B2, and to a lesser extent the dinitroso-epicatechin, also induced significant toxic effects in Caco-2 cells. The inhibitory effects on cellular proliferation were paralleled by early inhibition of ERK 1/2 phosphorylation and later reductions in cyclin D1 levels, indicating modulation of cell cycle regulation in Caco-2 cells. These effects highlight multiple routes in which dietary derived flavanols may exert beneficial effects in the gastrointestinal tract.
Lee
Stephanie Y H
SY
Molucular Nutrition Group, School of Biosciences, University of Reading, Reading RG2 6AP, UK.
Munerol
Bibiana
B
Pollard
Susan
S
Youdim
Kuresh A
KA
Pannala
Ananth S
AS
Kuhnle
Gunter G C
GG
Debnam
Edward S
ES
Rice-Evans
Catherine
C
Spencer
Jeremy P E
JP
D000042:Absorption; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D004128:Dimethylnitrosamine; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D041981:Gastrointestinal Tract / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D009602:Nitrosamines / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D009603:Nitroso Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D009608:Nitrous Acid / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D026361:Reactive Nitrogen Species / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism
D005419:Flavonoids; D009602:Nitrosamines; D009603:Nitroso Compounds; D010636:Phenols; D026361:Reactive Nitrogen Species; C509373:epicatechin dimer B2; D019938:Cyclin D1; C002744:3-nitrotyrosine; D014443:Tyrosine; D002392:Catechin; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D004128:Dimethylnitrosamine; D009608:Nitrous Acid