INFLUENCE OF PEROXISOME PROLIFERATORS ON PHOSPHOPROTEIN LEVELS IN HUMAN AND RAT HEPATIC-DERIVED CELL-LINES

To elucidate the effect of peroxisome proliferators on the signal-tran sduction pathway, we have compared the effect of ciprofibrate, an hypo lipaemic agent, on the overall phosphoprotein level between rat and hu man well differentiated hepatic derived cell lines. The phosphorylatio n status of several phosphoproteins in the rat Fao cell line was incre ased by the drug while no changes were observed in the human HepG2 cel l line. In rat Fao cells, this increase, which is concentration and ti me dependent, can be as much as eightfold for 20-kDa and 22-kDa protei ns. Wy-14,643, a non-fibrate molecule and a more potent peroxisome pro liferator than ciprofibrate, increased the phosphorylation status of t he same phosphoproteins. Peroxisome proliferators may act by activatin g kinases inactive in control cells, by amplifying kinases already act ive in control cells or by inactivating phosphatases. The phosphoamino acid residues affected are essentially serine and threonine. This mod ification of the signal-transduction pathway by the peroxisome prolife rators in rodent cells appears to be an early event or an independent mechanism of the peroxisome proliferation. These results support the a ccumulating evidence that the perturbation of this pathway may be a ma jor cause of the hepatomegaly and the hepatocarcinogenesis induced by peroxisome proliferators in rodent species. In contrast, the lack of p hosphorylation changes in the human HepG2 cell line supports the non-t oxic effect of peroxisome proliferators also used as hypolipaemic agen ts in humans.