title: Dose-dependent metabolic disposition of hydroxytyrosol and formation of mercapturates in rats.
abstract: Hydroxytyrosol (HT), one of the major polyphenols present in olive oil, is known to possess a high antioxidant capacity. The aim of the present study was to investigate dose dependent (0, 1, 10 and 100 mg/kg) alterations in the metabolism of HT in rats since it has been reported that metabolites may contribute to biological effects. Special attention was paid to the activation of the semiquinone-quinone oxidative cycle and the formation of adducts with potential deleterious effects. Thus, we developed a novel analytical methodology to monitor the in vivo formation of the HT mercapturate, N-acetyl-5-S-cysteinyl-hydroxytyrosol in urine samples. Biomarkers of hepatic and renal toxicity were evaluated within the dose range tested. Following HT administration, dose-dependent effects were observed for the recovery of all the metabolites studied. At the lowest dose of 1 mg/kg, the glucuronidation pathway was the most relevant (25-30%), with lower recoveries for sulfation (14%), while at the highest dose of 100 mg/kg, sulfation was the most prevalent (75%). In addition, we report for the first time the formation of the mercapturate conjugate of HT in a dose-dependent manner. The biochemical data did not reveal significant toxic effects of HT at any of the doses studied. An increase in the GSH/GSSG ratio at the highest dose was observed indicating that the products of HT autoxidation are counteracted by glutathione, resulting in their detoxification. These results indicate that the metabolic disposition of HT is highly dependent on the dose ingested.
authors.affiliation: Human Pharmacology and Clinical Neurosciences Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain(1).
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Kotronoulas
authors.forename: Nieves
authors.initials: N
authors.lastname: Pizarro
authors.forename: Aida
authors.initials: A
authors.lastname: Serra
authors.forename: Patricia
authors.initials: P
authors.lastname: Robledo
authors.forename: Jesús
authors.initials: J
authors.lastname: Joglar
authors.forename: Laura
authors.initials: L
authors.lastname: Rubió
authors.forename: Alvaro
authors.initials: A
authors.lastname: Hernaéz
authors.forename: Carmen
authors.initials: C
authors.lastname: Tormos
authors.forename: Ma José
authors.initials: MJ
authors.lastname: Motilva
authors.forename: Montserrat
authors.initials: M
authors.lastname: Fitó
authors.forename: Maria-Isabel
authors.initials: MI
authors.lastname: Covas
authors.forename: Rosa
authors.initials: R
authors.lastname: Solà
authors.forename: Magí
authors.initials: M
authors.lastname: Farré
authors.forename: Guillermo
authors.initials: G
authors.lastname: Saez
authors.forename: Rafael
authors.initials: R
authors.lastname: de la Torre
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism* / Q000652:urine; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000652:urine; D019803:Glutathione Disulfide / Q000652:urine; D008297:Male; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity / Q000652:urine; D059808:Polyphenols / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D051381:Rats
chemical_list: D000975:Antioxidants; D059808:Polyphenols; C005975:3,4-dihydroxyphenylethanol; D005978:Glutathione; D010626:Phenylethyl Alcohol; D019803:Glutathione Disulfide; D000111:Acetylcysteine
keywords: Gluc; Glutathione; HOPhPr; HT; HT-NAC; HTAc; HVAlc; Hydroxytyrosol metabolism; Mercapturate adducts; N-acetyl-5-S-cysteinyl hydroxytyrosol; Oxidative damage; Polyphenols; Sulf; glucuronide; homovanillyl alcohol; hydroxyphenylpropanol; hydroxytyrosol; hydroxytyrosol acetate; sulfate