Peroxisome proliferators induce apoptosis and decrease DNA synthesis in hepatoma cell lines

We examined the effects of various peroxisome proliferators (PPs) such as t he hypolipidaemic agents clofibric acid (CLO), bezafibrate (BEZA), ciprofib rate (CIPRO) and nafenopin (NAFE) and the plasticizer di-(2-ethylhexyl)phth alate (DEHP) on peroxisomal enzyme activities, apoptosis and DNA synthesis in rat FaO and human HepG2 hepatoma cell lines. Both growing and confluent cultures were treated with PPs (250 mu M) for 48 or 72 h. In accordance wit h our previous observations in PP-treated primary hepatocyte cultures of ra t and human origin,(1) the various PPs increased peroxisomal enzyme activit ies in rat FaO cells bat not in human HepG2 cells. PPs strongly induced apo ptosis in FaO cells. They did not affect TGF beta-induced apoptosis, with t he exception of DEHP and NAFE, respectively blocking and increasing induced apoptosis in confluent cultures. Moreover, PPs produced a minor, but signi ficant, decrease in DNA synthesis in FaO cells. PPs also decreased DNA synt hesis in growing HepG2 cells, and CLO, CIPRO and NAFE induced apoptosis in confluent HepG2 cultures. This is in opposition with the effects of PPs on primary hepatocyte cultures, i.e. inhibition of both spontaneous and TGF be ta-induced apoptosis and increases in DNA synthesis in rat hepatocytes, and unchanged mitosis-apoptosis balance in human hepatocytes.(1).