Effects of the peroxisome proliferator clofibric acid on superoxide dismutase expression in the human HepG2 hepatoma cell line

We examined the effects of clofibric acid, a peroxisome proliferator, on th e production of superoxide radicals, on the levels of malondialdehyde (MDA) and 4-hydroxynonenal (LC-HNE), and on the expression of superoxide dismuta ses (SODs) in the human HepG2 hepatoma cell line. To this end, HepG2 cells were treated for 1 or 5 days with 0.25, 0.50, or 0.75 mM clofibric acid. Th e production of superoxide radicals was only enhanced in HepG2 cells expose d for 5 days to the different clofibric acid concentrations. However, this overproduction of superoxide radicals was not accompanied by increased rate s of lipid peroxidation, as the MDA and 4-HNE levels did not change signifi cantly. Manganese (Mn) SOD activity was increased when HepG2 cells were tre ated for 1 day with 0.50 or 0.75 mM clofibric acid. For this duration of tr eatment, no change was observed in total SOD and copperizinc (Cu/Zn) SOD ac tivities. For a 5 day treatment, total SOD and MnSOD activities as well as the enzyme apoprotein and MnSOD mRNA levels increased whatever the clofibri c acid concentration used. This transcriptional induction of the MnSOD gene was correlated with an activation of the activator protein-1 transcription factor for 1 and 5 days of treatment, but was independent of nuclear facto r-kappa B and of peroxisome proliferator-activated receptor. On the other h and, the PP exerted very little effect if any on Cu,ZnSOD expression. In co ntrast to rodent data, PP treatment of human hepatoma cells induces MnSOD e xpression. 1999. (C) 1999 Elsevier Science Inc.