Clofibric acid down-regulation of metallothionein IIA in HepG2 human hepatoma cells

• Published in: Biochemical pharmacology 2002-01, Vol.63 (2), p.237-245
• Main Authors: Bianchi, Arnaud, Bécuwe, Philippe, Collet, Philippe, Keller, Jean Marie, Domenjoud, Lionel, Dauça, Michel
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Carcinoma, Hepatocellular; Clofibric acid; Clofibric Acid - pharmacology; Down-Regulation - drug effects; Gene expression; Gene Expression Regulation - drug effects; General and cellular metabolism. Vitamins; Human hepatoma cells; Humans; Hypolipidemic Agents - pharmacology; Liver Neoplasms; Medical sciences; Metallothionein; Metallothionein - genetics; Metallothionein - metabolism; Peroxisome proliferators; Pharmacology. Drug treatments; PPAR; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - physiology; Receptors, Cytoplasmic and Nuclear - metabolism; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Transcription Factors - metabolism; Tumor Cells, Cultured
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(01)00863-2

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 PPARα expression vector. These results provide new insights about the pleiotropic effects of PPs on human cells.