Cytoprotective properties of alpha-tocopherol are related to gene regulation in cultured D-galactosamine-treated human hepatocytes.
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.
González
Raul
R
Liver Research Unit, Reina Sofía University Hospital, Ciberehd, E-14004 Córdoba, Spain.
Collado
Juan Antonio
JA
Nell
Sandra
S
Briceño
Javier
J
Tamayo
María José
MJ
Fraga
Enrique
E
Bernardos
Angel
A
López-Cillero
Pedro
P
Pascussi
Jean Marc
JM
Rufián
Sebastián
S
Vilarem
Marie-José
MJ
De la Mata
Manuel
M
Brigelius-Flohe
Regina
R
Maurel
Patrick
P
Muntané
Jordi
J
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*
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