Hepatotrophic Properties in Dogs of Human Fkbp, the Binding Protein for Fk506 and Rapamycin

Cyclosporine and FK506 have been shown with two experimental models to influence liver structure, function, and the capacity for regeneration.Both drugs augment the liver regeneration in rats that is the normal response to partial hepatectomy (1).In addition, the increase in hepatocyte replication that is caused by portacaval shunt in dogs is more than doubled by intrahepatic infusion of these drugs via the tied-off central portal vein.Also, the atrophy and organelle disruption caused by portacaval shunt is prevented (2, 3).Immune modulation of lymphocytes and NK cells as an explanation for these so-called "hepatotrophic" effects has been ruled out by direct experimentation in nude rats (4).The foregoing findings, as well as observations of manifold metabolic effects in patients treated either with FK506 or with cyclosporine, have led to a hypothesis that these drugs modify signal transduction in a variety of cells, not limited to those of the immune system (3, 5).Consistent with the hypothesis is the recent demonstration that FK506 and cyclosporine inhibit signaling processes in the mast cell at concentrations similar to those used to block signaling pathways in T cells (6; also Schreiber SL, et al., unpublished observations).Central to the signal transduction hypothesis was the discovery that the cytosolic receptors for FK506 and rapamycin (FK506-binding protein, FKBP)* and cyclosporine (cyclophilin) are distinct proteins that exhibit peptidyl-prolyl cis trans isomerase (rotamase) activity (7, 8).Rotamases have been shown to facilitate protein folding (9, 10) and to catalyze the interconversion of