Hepatic clearance of gastrin and cholecystokinin peptides

The purpose of this study was to examine and quantify hepatic uptake and degradation of gastrin and cholecystokinin peptides. Rat livers were perfused in situ, without recirculation, with Krebs-Ringer bicarbonate (pH 7.4) containing 10% bovine erythrocytes, gassed with 95% O2-5% CO2. Gastrin and cholecystokinin peptide fragments of various lengths were injected into a portal vein via a sidearm syringe for over 1 min, and hepatic venous effluent was collected every minute for 20 min. After injection of 125I-labeled gastrin peptides more than eight amino acids in length, greater than 95% radioactivity appeared in the hepatic venous effluent, all of which was intact peptide, as determined by immunoprecipitation, trichloroacetic acid precipitation, and Sephadex gel chromatography. Decreasing the chain length to eight or less amino acids resulted in progressive increases in hepatic uptake and degradation of gastrin fragments. Injected cholecystokinin peptides greater than seven amino acids in length traversed the liver intact, whereas smaller cholecystokinin peptides were cleared by the liver. The liver eliminated greater than 90% of the biologically active carboxyl-terminal tetrapeptide amide common to gastrin and cholecystokinin. The results of this study indicate that gastrin and cholecystokinin peptides longer than seven amino acids traverse the liver without significant degradation, however, smaller peptides are progressively cleared during hepatic transit. Therefore, if small gastrin and cholecystokinin peptides from antral and intestinal mucosa are released and reach the portal venous circulation, hepatic inactivation would appear to prevent them from reaching the systemic circulation, precluding their significant contribution to gastric acid secretion and other physiologic functions.