AbstractReduced hepatic uptake and clearance of macromolecules in liver cirrhosis is due to two major factors: increased diffusional barriers, resulting primarily from the deposition of excessive connective tissue in the space of Disse, and hepatocellular dysfunction, manifested by receptor and/or postreceptor defects.To probe the mechanisms underlying hepatocellular dysfunction in liver cirrhosis, we have investigated receptor‐ligand interactions for asialoorosomucoid, insulin and epidermal growth factor in hepatocytes isolated from the livers of rats chronically exposed to phenobarbital and carbon tetrachloride for up to 12 weeks. Viable cells were allowed to attach at 37°C and the high‐affinity cell surface binding sites for each ligand were assessed at 4°C in the presence of [125I]‐ligand. In parallel incubations, digitonin (0.055%) was added to the binding medium to assess total cellular binding sites.Results demonstrated that chronic treatment of rats with phenobarbital increased hepatocyte asialoorosomucoid surface receptor affinity (p<0.05) but had no affect on the number of asialoglycoprotein binding sites. Treatment with CCl4and phenobarbital significantly reduced the number of surface binding sites for asialoorosomucoid (p<0.05) and epidermal growth factor (p<0.02), although this treatment had no effect on either the binding affinity or the number of binding sites for insulin. The decrease in cell surface binding sites for asialoorosomucoid and epidermal growth factor was not due to a redistribution of the surface sites to intracellular locations, since the total number of cellular binding sites also was reduced. These results indicate that cirrhosis induced by phenobarbital and CCl4results in a differential effect on one parameter of hepatocellular function: receptor‐ligand in