title: Cytoprotective properties of alpha-tocopherol are related to gene regulation in cultured D-galactosamine-treated human hepatocytes.
abstract: Vitamin E (alpha-tocopherol) has demonstrated antioxidant activity and gene-regulatory properties. d-Galactosamine (D-GalN)-induced cell death is mediated by nitric oxide in hepatocytes, and it is associated with hepatic steatosis. The beneficial properties of alpha-tocopherol and their relation to oxidative stress and gene regulation were assessed in D-GalN-induced cell death. Hepatocytes were isolated from human liver resections by a collagenase perfusion technique. alpha-Tocopherol (50 microM) was administered at the advanced stages (10 h) of D-GalN-induced cell death in cultured hepatocytes. Cell death, oxidative stress, alpha-tocopherol metabolism, and NF-kappaB-, pregnane X receptor (PXR)-, and peroxisome proliferator-activated receptor (PPAR-alpha)-associated gene regulation were estimated in the hepatocytes. D-GalN increased cell death and alpha-tocopherol metabolism. alpha-Tocopherol exerted a moderate beneficial effect against apoptosis and necrosis induced by D-GalN. Induction (rifampicin) or inhibition (ketoconazole) of alpha-tocopherol metabolism and overexpression of PXR showed that the increase in PXR-related CYP3A4 expression caused by alpha-tocopherol enhanced cell death in hepatocytes. Nevertheless, the reduction in NF-kappaB activation and inducible nitric oxide synthase expression and the enhancement of PPAR-alpha and carnitine palmitoyl transferase gene expression by alpha-tocopherol may be relevant for cell survival. In conclusion, the cytoprotective properties of alpha-tocopherol are mostly related to gene regulation rather than to antioxidant activity in toxin-induced cell death in hepatocytes.
authors.affiliation: Liver Research Unit, Reina Sofía University Hospital, Ciberehd, E-14004 Córdoba, Spain.
authors.forename: Raul
authors.initials: R
authors.lastname: González
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Collado
authors.forename: Sandra
authors.initials: S
authors.lastname: Nell
authors.forename: Javier
authors.initials: J
authors.lastname: Briceño
authors.forename: María José
authors.initials: MJ
authors.lastname: Tamayo
authors.forename: Enrique
authors.initials: E
authors.lastname: Fraga
authors.forename: Angel
authors.initials: A
authors.lastname: Bernardos
authors.forename: Pedro
authors.initials: P
authors.lastname: López-Cillero
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Pascussi
authors.forename: Sebastián
authors.initials: S
authors.lastname: Rufián
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Vilarem
authors.forename: Manuel
authors.initials: M
authors.lastname: De la Mata
authors.forename: Regina
authors.initials: R
authors.lastname: Brigelius-Flohe
authors.forename: Patrick
authors.initials: P
authors.lastname: Maurel
authors.forename: Jordi
authors.initials: J
authors.lastname: Muntané
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019610:Cytoprotection; D005688:Galactosamine / Q000037:antagonists & inhibitors / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics; D047493:PPAR alpha / Q000378:metabolism; D000077297:Pregnane X Receptor; D017382:Reactive Oxygen Species / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D024502:alpha-Tocopherol / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D047493:PPAR alpha; D000077297:Pregnane X Receptor; D017382:Reactive Oxygen Species; D011987:Receptors, Steroid; D005688:Galactosamine; D003577:Cytochrome P-450 Enzyme System; D052247:Nitric Oxide Synthase Type II; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D002334:Carnitine O-Palmitoyltransferase; D024502:alpha-Tocopherol