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.

This work was supported by grants from Instituto de Salud Carlos III FEDER, (PI14/00072), the CICYT-FEDER (AGL2009-13517- C03-01 and AGL2012-40144-C03-01), grants from DIUE of the Generalitat de Catalunya (2014 SGR 680). CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of the Instituto de Salud Carlos III, Madrid, Spain. JRM was supported by a FI-DGR2012 predoctoral fellowship from the Generalitat de Catalunya and CPM was supported by a Juan Rodés fellowship (ISCIII, JR, 15/00005). The authors acknowledge the support received from National Institutes of Health grant DA U01 020830, Canadian Institutes of Health Research grant MOP86471, the Endowed Chair in Addiction for the Department of Psychiatry University of Toronto (RFT), and funds from the Centre for Addiction and Mental Health (CAMH) and the CAMH Foundation (RFT)