A critical examination of human data for the biological activity of phenolic acids and their phase-2 conjugates derived from dietary (poly)phenols, phenylalanine, tyrosine and catecholamines

Free or conjugated aromatic/phenolic acids arise from the diet, endogenous metabolism of catecholamines (adrenaline, noradrenaline, dopamine), protein (phenylalanine, tyrosine), pharmaceuticals (aspirin, metaprolol) plus gut microbiota metabolism of dietary (poly)phenols and undigested protein. Quantitative data obtained with authentic calibrants for 112 aromatic/phenolic acids including phase-2 conjugates in human plasma, urine, ileal fluid, feces and tissues have been collated and mean/median values compared with in vitro bioactivity data in cultured cells. Ca 30% of publications report bioactivity at ≤1 μmol/L. With support from clinical studies, it appears that the greatest benefit might be produced in vascular tissues by C₆-C₃ metabolites, including some of gut microbiota origin and some phase-2 conjugates, 15 of which are 3',4'-disubstituted with multiple sources including caffeic acid and hesperetin, plus one unsubstituted and two mono-substituted examples which can originate from protein. There is an unexamined potential for synergy. Free-living and washout plasma data are scarce. Some metabolites have been overlooked, notably phenyl-lactic, phenyl-hydracrylic and phenyl-propanoic acids, especially those from amino acids plus glycine, hydroxy-glycine and glutamine conjugates. Phenolic acids and conjugates from multiple sources exhibit biological activities, some of which are likely relevant in vivo and link to biomarkers of health. Further targeted studies are justified.