xact direction nor the magnitude of a transform in such activity could be precisely predicted on the sole basis of the chemical nature of a flavonoid [98], theoretically, it might be HDAC10 custom synthesis expected that nu blocking via methylation, sulfation or glucuronidation, one particular or more of its redox-active phenolic groups, for example, a single phenolic, catechol or galloyl in ring B, would compromise the flavonoid’s original antioxidant properties [61,99,100]. InAntioxidants 2022, 11,6 ofAntioxidants 2022, 11, x FOR PEER REVIEW6 offact, most studies indicate that when such a variety of metabolites are assayed in vitro for their ROS-scavenging/reducing activity, these have either drastically lost or only marginally retained the antioxidant activity of their precursors, but that in no case have they undergone liver by way of the portal vein, they circulate in systemic blood virtually exclusively as O-glucua substantial KDM4 review achieve of such activity [74,96,10112]. Essentially, equivalent in vitro results have ronide, O-sulphate and/or O-methyl ester/ether metabolites (commonly in this order of recently been reported regarding the capacity of some flavonoids’ phase II-conjugation abundance) [69,90]. metabolites to upregulate (by way of an indirect action) the cell’s endogenous antioxidant capacity [80,11315] (Table 1). It need to be noted, nevertheless, that in some particular circumstances, Table 1. Phenol-compromising reactions. As exemplified for quercetin (Q), the primary reactions that impact the redox-active phase I and/or II biotransformation metabolites happen to be shown to exert quite a few phenol moieties of quercetin are listed. Moreover, the chemical nature of some of the formed metabolites and the influence other, not necessarily the antioxidant properties biological actions that could that the phenol-compromising reactions can have onantioxidant-dependent, on the metabolites are described. substantially contribute to the health-promoting effects of their precursor flavonoids [79,116,117]. Phenol Effect on Metabolites Compromising Reactions Table 1. Phenol-compromising reactions. As exemplified for quercetin (Q), the primary reactions that Antioxidant Potency have an effect on the redox-active phenol moieties of quercetin are general, these metabolites have much less of Glycosides (e.g. Q-3-O-glucoside; Q-4-OIn listed. Also, the chemical nature O-Glycosylation a number of the formed metabolites Q-5-O-glucoside the ROS-scavenging potency than their on along with the influence that phenol-compromising reactions can have glucoside; 3,4-O-diglucoside; (in plants) the antioxidant properties from the metabolites are described. and Q-7-O-glucoside) corresponding aglycones The ROS-scavenging potency of OPhenol O-Deglycosylation Quercetin O-deglycosylated in C3, C4 C5 or Impact on Compromising Metabolites deglycosylated metabolites is, in most Antioxidant Potency (in human intestine/colon) C7 Reactions instances, considerably larger These In general, these metabolites have much less metabolites have, in general, significantly less O-Glycosylation Glycosides (e.g., Q-3-O-glucoside; Q-4 -O-glucoside; ROS-scavenging potency than their Glucuronides (e.g. Q-3-O- and Q-7-O(in plants) 3,4 -O-diglucoside; Q-5-O-glucoside and Q-7-O-glucoside) ROS scavenging/reduction potency but in Biotransformation corresponding aglycones glucuronides) some specific cases are in a position to up(in human intestine/ O-Deglycosylation The ROS-scavenging potency of Sulphates (e.g. Q-3-O-andin C3, C4 , C5 or C7 Q-3′-O-sulphates) (in human Quercetin O-deglycosylated O-deglycosylated meta