How do nutritional antioxidants really work: Nucleophilic tone and para-hormesis versus free radical scavenging in vivo

•Assumptions of free radical scavenging by antioxidants in vivo are kinetically unsound.•Among natural antioxidants, only vitamin E has the potential to act in vivo.•Electrophilic antioxidants and electrophiles derived from polyphenols increase nucleophilic tone.•Nucleophilic tone is the overall potential cellular adaptive response to oxidative challenge brought by electrophiles.•Electrophiles induce nucleophilic tone through activation of Nrf2.

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.

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