CYP2D6 and CYP2A6 biotransform dietary tyrosol into hydroxytyrosol.
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.
Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, IMIM (Hospital del Mar Medical Research Institute), Dr. Aiguader 88, Barcelona 08003, Spain; Department of Experimental and Health Sciences, Universitat Pompeu Fabra (CEXS-UPF), Dr. Aiguader 80, Barcelona 08003, Spain; Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto Salud Carlos III, 28029 Madrid, Spain. Electronic address: jrodriguez1@imim.es.
Jose
J
Rodríguez-Morató
Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, IMIM (Hospital del Mar Medical Research Institute), Dr. Aiguader 88, Barcelona 08003, Spain; Department of Experimental and Health Sciences, Universitat Pompeu Fabra (CEXS-UPF), Dr. Aiguader 80, Barcelona 08003, Spain. Electronic address: probledo@imim.es.
Patricia
P
Robledo
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, Toronto, Ontario, Canada. Electronic address: julieanne.tanner@mail.utoronto.ca.
Julie-Anne
JA
Tanner
Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, IMIM (Hospital del Mar Medical Research Institute), Dr. Aiguader 88, Barcelona 08003, Spain; Department of Experimental and Health Sciences, Universitat Pompeu Fabra (CEXS-UPF), Dr. Aiguader 80, Barcelona 08003, Spain. Electronic address: aboronat@imim.es.
Anna
A
Boronat
Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, IMIM (Hospital del Mar Medical Research Institute), Dr. Aiguader 88, Barcelona 08003, Spain; Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, Cerdanyola, Spain. Electronic address: cperez@imim.es.
Clara
C
Pérez-Mañá
Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, Cerdanyola, Spain; Antioxidants Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, United States. Electronic address: Oliver.Chen@tufts.edu.
C-Y
CY
Oliver Chen
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, Toronto, Ontario, Canada; Department of Psychiatry, Toronto, Ontario, Canada. Electronic address: r.tyndale@utoronto.ca.
Rachel F
RF
Tyndale
Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, IMIM (Hospital del Mar Medical Research Institute), Dr. Aiguader 88, Barcelona 08003, Spain; Department of Experimental and Health Sciences, Universitat Pompeu Fabra (CEXS-UPF), Dr. Aiguader 80, Barcelona 08003, Spain; Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto Salud Carlos III, 28029 Madrid, Spain. Electronic address: rtorre@imim.es.
Rafael
R
de la Torre
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001711:Biotransformation; D065637:Cytochrome P-450 CYP2A6 / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000378:metabolism
D000975:Antioxidants; C005975:3,4-dihydroxyphenylethanol; C011867:4-hydroxyphenylethanol; D014443:Tyrosine; D065637:Cytochrome P-450 CYP2A6; D019389:Cytochrome P-450 CYP2D6; D010626:Phenylethyl Alcohol
CYP2A6; CYP2D6; Coumarin (PubChem CID: 323); Dextromethorphan (PubChem CID: 6916184); Human liver microsomes; Hydroxytyrosol; Hydroxytyrosol (PubChem CID: 82755); Metabolism; Methoxsalen (PubChem CID: 4114); Nicotine (PubChem CID: 942); Tranylcypromine (PubChem CID: 19493); Tryptamine (PubChem CID: 1150); Tyrosol; Tyrosol (PubChem CID: 10393)