CYP2D6 and CYP2A6 biotransform dietary tyrosol into hydroxytyrosol

Abstract

The dietary phenol tyrosol has been reported to be endogenously transformed into hydroxytyrosol, a potent antioxidant with multiple health benefits. In this work, we evaluated whether tyrosine hydroxylase (TH) and cytochrome P450s (CYPs) catalyzed this process. To assess TH involvement, Wistar rats were treated with α-methyl-L-tyrosine and tyrosol. Tyrosol was converted into hydroxytyrosol whilst α-methyl-L-tyrosine did not inhibit the biotransformation. The role of CYP was assessed in human liver microsomes (HLM) and tyrosol-to-hydroxytyrosol conversion was observed. Screening with selective enzymatic CYP inhibitors identified CYP2A6 as the major isoform involved in this process. Studies with baculosomes further demonstrated that CYP2D6 and CYP3A4 could transform tyrosol into hydroxytyrosol. Experiments using human genotyped livers showed an interindividual variability in hydroxytyrosol formation and supported findings that CYP2D6 and CYP2A6 mediated this reaction. The dietary health benefits of tyrosol-containing foods remain to be evaluated in light of CYP pharmacogenetics.

Probing Downstream Olive Biophenol Secoiridoids

“…Furthermore, the liver cytochrome P450s, including CYP2D6 and CYP3A4, transformed tyrosol into hydroxytyrosol, which can contribute to therapeutic potential [ 58 ]. However, oleuropein was poorly or dose-dependently absorbed, and inhibited CYP3A [ 59 , 60 , 61 ]. Therefore, the tested olive BPseco downstream pathway in this study emphasizes their stability toward hydrolysis under simulated experimental conditions and TNDO mechanisms that are alike in olive milling processing and in the human gastrointestinal tract.…”

Variation in CYP2A6 Activity and Personalized Medicine

“…The dietary phenol tyrosol, found in red wine, olives, and olive oil, is metabolized to hydroxytyrosol by CYP2A6, with minor contributions of CYP2D6 and CYP3A4 [ 186 ]. Both tyrosol and hydroxytyrosol have antioxidant effects; however, the metabolite, hydroxytyrosol, appears to exhibit greater antioxidant activity than tyrosol [ 187 ], suggesting that individuals with faster CYP2A6 enzyme activity and associated genotypes may benefit most from consumption of tyrosol-containing foods.…”

Wine and Olive Oil Phenolic Compounds Interaction in Humans

“…Although there is a contribution of dopamine and tyrosine when alcohol is consumed in the formation of HT and TYR, this does not suffice to explain recoveries of HT and TYR [ 19 ]. We demonstrated in vivo, in animal models, and in vitro, in human liver biopsies, that the most likely explanation for higher recoveries of both phenolic compounds is the biotransformation of TYR to HT, a reaction regulated by the polymorphic enzymes CYP2D6 and CYP2A6 [ 20 ]. Ethanol contributes to this reaction by increasing TYR bioavailability and then favoring the biotransformation reaction.…”

“…Further pre-clinical studies identified TYR as the metabolic precursor of HT [ 19 ]. TYR is endogenously bio transformed in humans into HT by means of the isoforms CYP2A6 and CYP2D6 [ 20 ]. HT endogenous generation after RW consumption could, in part, explain the beneficial effects derived from moderate wine consumption [ 17 ].…”