title: Hydroxytyrosol glucuronides protect renal tubular epithelial cells against H(2)O(2) induced oxidative damage.
abstract: Hydroxytyrosol (2-(3',4'-dihydroxyphenyl)ethanol; HT), the most active ortho-diphenolic compound, present either in free or esterified form in extravirgin olive oil, is extensively metabolized in vivo mainly to O-methylated, O-sulfated and glucuronide metabolites. We investigated the capacity of three glucuronide metabolites of HT, 3'-O-β-d-glucuronide and 4'-O-β-d-glucuronide derivatives and 2-(3',4'-dihydroxyphenyl)ethanol-1-O-β-d-glucuronide, in comparison with the parent compound, to inhibit H(2)O(2) induced oxidative damage and cell death in LLC-PK1 cells, a porcine kidney epithelial cell line. H(2)O(2) treatment exerted a toxic effect inducing cell death, interacting selectively within the pro-death extracellular-signal relate kinase (ERK 1/2) and the pro-survival Akt/PKB signaling pathways. It also produced direct oxidative damage initiating the membrane lipid peroxidation process. None of the tested glucuronides exhibited any protection against the loss in renal cell viability. They also failed to prevent the changes in the phosphorylation states of ERK and Akt, probably reflecting their inability to enter the cells, while HT was highly effective. Notably, pretreatment with glucuronides exerted a protective effect at the highest concentration tested against membrane oxidative damage, comparable to that of HT: the formation of malondialdehyde, fatty acid hydroperoxides and 7-ketocholesterol was significantly inhibited.
authors.affiliation: Dipartimento di Biologia Sperimentale, Sezione di Patologia Sperimentale, Università degli Studi di Cagliari, Cittadella Universitaria, Monserrato, Italy. mdeiana@unica.it
authors.forename: Monica
authors.initials: M
authors.lastname: Deiana
authors.forename: Alessandra
authors.initials: A
authors.lastname: Incani
authors.forename: Antonella
authors.initials: A
authors.lastname: Rosa
authors.forename: Angela
authors.initials: A
authors.lastname: Atzeri
authors.forename: Debora
authors.initials: D
authors.lastname: Loru
authors.forename: Barbara
authors.initials: B
authors.lastname: Cabboi
authors.forename: M
authors.initials: M
authors.lastname: Paola Melis
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lucas
authors.forename: Juan C
authors.initials: JC
authors.lastname: Morales
authors.forename: M
authors.initials: M
authors.lastname: Assunta Dessì
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D020719:Glucuronides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007653:Ketocholesterols / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology; D008054:Lipid Peroxides / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine
chemical_list: D000975:Antioxidants; D020719:Glucuronides; D007653:Ketocholesterols; D008054:Lipid Peroxides; C005975:3,4-dihydroxyphenylethanol; D008315:Malondialdehyde; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010626:Phenylethyl Alcohol; C003001:7-ketocholesterol