title: Clofibric acid down-regulation of metallothionein IIA in HepG2 human hepatoma cells.
abstract: Among the different hypotheses advanced to explain the peroxisome proliferator (PP)-induced hepatocarcinogenicity in rodents, one is based on the development of an oxidative stress due to an imbalance in the production of reactive oxygen species that leads to DNA damages and lipid peroxidation. On the other hand, human cells appear to be nonresponsive to PPs. As metallothionein proteins play an important antioxidant role, the aim of the present study was to investigate the expression of metallothionein IA (MTIA) and IIA (MTIIA) in HepG2 human hepatoma cells exposed to clofibric acid. When HepG2 cells were treated for 24 hr with 0.50 or 0.75 mM CA, a significant decrease was observed in MT protein-level determined by Western blotting and in the MTIIA mRNA content analyzed by RT-PCR and Northern blotting. No significant change was observed in the MTIA mRNA amount whatever the CA concentration and the duration of treatment. The decrease in MTIIA mRNA-level was not mediated via peroxisome proliferator-activated receptor alpha as attested by our data from gel mobility shift DNA binding assays, Dot blotting and cotransfection experiments with MTIIA promoter-driven luciferase reporter gene and PPARalpha expression vector. These results provide new insights about the pleiotropic effects of PPs on human cells.
authors.affiliation: Laboratoire de Biologie Cellulaire du Development, Ea 3446, Proliferateurs de Peroxysomes, Faculte des Sciences, Universite Henri Poincare Nancy I, B.P. 239, 54506, Vandoeuvre-les-Nancy, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bianchi
authors.forename: Philippe
authors.initials: P
authors.lastname: Bécuwe
authors.forename: Philippe
authors.initials: P
authors.lastname: Collet
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Keller
authors.forename: Lionel
authors.initials: L
authors.lastname: Domenjoud
authors.forename: Michel
authors.initials: M
authors.lastname: Dauça
mesh_terms: D006528:Carcinoma, Hepatocellular; D002995:Clofibric Acid / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008113:Liver Neoplasms; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D002995:Clofibric Acid; D008668:Metallothionein