HUMAN HEPG2 AND RAT FAO HEPATIC-DERIVED CELL-LINES SHOW DIFFERENT RESPONSES TO CIPROFIBRATE, A PEROXISOME PROLIFERATOR - ANALYSIS BY FLOW-CYTOMETRY

Peroxisome proliferators, and especially hypolipidemic drugs such as c iprofibrate, are known to be hepatocarcinogens in rodents, but their e ffect in humans is controversial. In an attempt to investigate the eff ects of ciprofibrate at a cellular level, the analysis of individual w hole cells was performed by flow cytometry on samples from two hepatic -derived cell lines: the rat Fao cell line and the human HepG2 cell li ne. The increase of light scatter signals in rat Fao cells treated for 3 days with ciprofibrate at 250 mu M was related to modifications of intrinsic cellular parameters, such as size and cytoplasmic granularit y, Conversely, no variations appeared in human HepG2-treated cells. Mo reover, the study of the cell cycle distribution of asynchronously gro wing cells showed an increase in the percentage of proliferative cells in Fao-treated cells, but not in HepG2-treated cells. In order to giv e a simultaneous assessment of changes in cellular parameters and cell metabolism, these flow cytometric experiments were completed with the measurements of the palmitoyl-CoA oxidase activity, used as a marker of peroxisome proliferation. The cellular modifications in the rat Fao cell line were accompanied by a great increase in this enzymatic acti vity, whereas the human HepG2 cell line, which failed to exhibit chang es of cytometric data, presented no, or weak, increase in this oxidase activity, The cellular modifications observed in the rat Pao cell lin e may be related to the well-known hepatocarcinogenicity of ciprofibra te in rodents, whereas the absence of response of HepG2 cells is in fa vor of the noncarcinogenicity of this drug in humans. This report vali dates another methodological approach for the investigation of the saf ety of peroxisome proliferators in humans. (C) 1996 Academic Press, In c.