Rapamycin, a potent immunosuppressive drug that disrupts normal signal-transduction processes, inhibited hepatocyte proliferation without evidence of inherent cytotoxicity in rat hepatocytes cultured in conventional medium or in a medium enriched with epidermal growth factor. The antiproliferative effect was dose dependent, uninfluenced by the concentration of epidermal growth factor in the medium and long lasting after a brief exposure. The effect of rapamycin was unaltered by the concomitant presence of FK 506 in the medium, suggesting that different binding affinities of these two drugs or even a separate rapamycin binding site may exist. Hepatocytes harvested 12 and 24 hr after partial hepatectomy were progressively less responsive to the antiproliferative effect of rapamycin. The gene expression of transforming growth factor8 was reduced under in uiuo rapamycin treatment, but at the same time the gene expression of albumin and glyceraldehyde-3-phosphate dehydrogenase was unchanged or increased. The experiments confirm that rapamycin has inherent growth-control qualities, and they strengthen the hypothesis that the recently defined immunophilin network is central to many aspects of cellular growth control. (HEPATOLOGY 1992; 15:871-877.)
In both rats and dogs, the immunosuppressive drugs cyclosporine (CYA) and FK 506 augment liver regeneration (1-4) and possess other hepatotrophic qualities (5, 6). In contrast, rapamycin (RPM), a powerful immunosuppressant that is chemically related to FK 506 but targeted to a different stage of T-cell activation (7, โฌ9, was recently shown to have antiproliferative properties, including inhibition of regeneration of the liver and of the intestine and kidney (9). We report here studies on the antiproliferative action of RPM on cultured rat hepatocytes in conventional medium, on hepatocytes in epidermal growth factor (EGFI-enriched medium and on hepatocytes harvested at different phases of the regeneration response. We also describe a selective