title: How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo.
abstract: We present arguments for an evolution in our understanding of how antioxidants in fruits and vegetables exert their health-protective effects. There is much epidemiological evidence for disease prevention by dietary antioxidants and chemical evidence that such compounds react in one-electron reactions with free radicals in vitro. Nonetheless, kinetic constraints indicate that in vivo scavenging of radicals is ineffective in antioxidant defense. Instead, enzymatic removal of nonradical electrophiles, such as hydroperoxides, in two-electron redox reactions is the major antioxidant mechanism. Furthermore, we propose that a major mechanism of action for nutritional antioxidants is the paradoxical oxidative activation of the Nrf2 (NF-E2-related factor 2) signaling pathway, which maintains protective oxidoreductases and their nucleophilic substrates. This maintenance of "nucleophilic tone," by a mechanism that can be called "para-hormesis," provides a means for regulating physiological nontoxic concentrations of the nonradical oxidant electrophiles that boost antioxidant enzymes, and damage removal and repair systems (for proteins, lipids, and DNA), at the optimal levels consistent with good health.
authors.affiliation: University of California, Merced, 5200 North Lake Road, Merced, CA 95343, USA; Andrus Gerontology Center of the Davis School of Gerontology, University of Southern, California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Forman
authors.affiliation: Andrus Gerontology Center of the Davis School of Gerontology, University of Southern, California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA; Division of Molecular & Computational Biology, Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA.
authors.forename: Kelvin J A
authors.initials: KJ
authors.lastname: Davies
authors.affiliation: Department of Molecular Medicine, University of Padova, Viale G. Colombo 3, I-35121, Padova, Italy. Electronic address: fulvio.ursini@unipd.it.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Ursini
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements; D000975:Antioxidants / Q000502:physiology*; D004032:Diet; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D059165:Hormesis; D006801:Humans; D015227:Lipid Peroxidation; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000502:physiology; D014810:Vitamin E / Q000502:physiology
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D014810:Vitamin E; D013482:Superoxide Dismutase; D005978:Glutathione
keywords: ARE; Antioxidants; EpRE; GSH; Glutathione; Keap1/Nrf2; Nrf2; Nucleophilic tone; Peroxidases; Redox signaling; SOD; Trx; antioxidant response element; electrophile response element; glutathione; nuclear factor erythroid 2-related factor 2; superoxide dismutase; thioredoxin