Recently, we described a new strategy for hepatocyte transplantation, using retrorsine/partial hepatectomy (PH) in a DPPIV- mutant Fischer rat model. Treatment of rats with retrorsine, a pyrrolizidine alkaloid, blocks endogenous hepatocytes from proliferating, so that after exposure to this agent coupled with PH and hepatocyte transplantation, transplanted hepatocytes selectively repopulate the liver. In the present study, we determined whether this method of cell transplantation can restore biosynthetic and physiological function in the liver by transplanting normal hepatocytes into rats genetically deficient in albumin synthesis, the Nagase analbuminic rat (NAR). After hepatocyte transplantation, albumin mRNA and protein were identified in the liver by in situ hybridization and immunohistochemistry, respectively, and serum albumin levels were determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, and enzyme-linked immunosorbent assay (ELISA) methods. At 1 month posttransplantation, large clusters of cells expressing albumin mRNA and protein were identified in the liver, representing approximately 50% of hepatocytes for albumin mRNA and approximately 61% for protein. At 2 months' posttransplantation, cells expressing albumin mRNA represented approximately 77% of hepatocyte mass, and cells expressing albumin protein represented approximately 81% of total hepatocyte mass. Hepatocyte-transplanted NAR also exhibited normal or near-normal serum albumin levels (3.0 +/- 0.2 g/dL). High levels of serum albumin were sustained for the 2-month duration of experiments. These results demonstrate the ability of this protocol for hepatocyte transplantation to restore a major biosynthetic and physiological function of the liver, and suggest its potential use as a method to treat genetic-based or acquired liver diseases.