shown by Zoete et al. [170], the HOMO power or electron-releasing energy (i.e., the easiness with which a molecule donates an electron and oxidizes) of 30 diverse polyphenols correlated well with their capacity to induce the EpRE-mediated gene transcription of NQO1, a phase II detoxifying enzyme known to become induced by Nrf2. In line with such results, Lee-Hilz et al. [54] also reported that the HOMO energy of 21 diverse flavonoids correlated effectively with their induction factor for the EpRE-mediated gene transcription. Based on these latter investigators, flavonoids with a larger intrinsic possible to create oxidative strain and redox cycling would be the most potent inducers of EpRE-mediated gene expression. More than the last decade, a considerable number of studies has demonstrated the capacity of some specific flavonoids to induce, by way of the activation from the Nrf2 eap1 program, the expression of c-Rel medchemexpress antioxidant and phase II detoxifying enzymes, in diverse cell models. Such an capacity would reside inside the capacity of such flavonoids to undergo enzymatic and/or non-enzymatic oxidation reactions that, at some point, convert them into electrophilic quinoid species (e.g., semi-quinones, and quinone methides) and/or specific ROS [17173]. The latter species is often generated for the duration of the interaction of some precise flavonoids (i.e., diphenols) with: (i) certain ROS (e.g., superoxide anions, hydroxyl and peroxyl radicals) given that just after scavenging or lowering them, the flavonoids are converted into phenoxyl radicals and potentially into quinoid species; (ii) catalytic concentrations of some redox-active transition metals which in, their lowered state (e.g., Cu1+ or Fe2+ ) and, presence of oxygen will generate superoxide anions that subsequently, via dismutation, will kind hydrogen peroxide; and (iii) specific metalloenzymes (e.g., peroxidases, tyrosinases, oxidoreductases) which can be capable to catalyze their oxidation, major to the formation of semiquinones and quinones. Inside the case of quercetin, shown to accumulate in huge amounts inside mitochondria [174], the formation of its quinone/quinone methide metabolites has been reported to take location not merely in peroxidase containing cell-free systems [175] but in addition in KDM1/LSD1 Formulation tyrosinase-rich cells (i.e., B16F-10, a mouse melanoma cell line) [171]. According to Awad et al. [171], the intracellular formation of these quinoid species could also take location in other mammalian cells known to contain peroxidase-like activities. Flavonoids that carry two or much more hydroxyl moieties in their B ring are recognized to become far more prone to kind quinoid intermediates, and consequently rank highest amongst the Nrf2-inducers. It should be noted, nevertheless, that some flavonoids that carry a single hydroxyl group in their B ring can be o-hydroxylated by human cytochrome P450 (CYP) enzymes to kind catechols within cells. As an example, CYP1 has been shown to catalyze the hydroxylation of kaempferol in B-3 , converting it into quercetin, and that of galangin in B-4 , converting it into kaempferol [85,176,177]. A further example would be the demethylation of four methoxyflavone catalyzed by human CYP1B1.1 and CYP1B1.three, which initially leads to the formation of four -hydroxyflavone and subsequently to that of 3 ,4 -dihydroxyflavone [178].Antioxidants 2022, 11,11 ofThus, it seems that, in humans, the oxidation of flavonoids can take spot via reactions catalyzed by CYP enzymes. These enzymes, even so, rather than inducing the oxidative consumption on the redox-active