Hepatic sequestration and biliary secretion of epidermal growth factor: evidence for a high-capacity uptake system

Epidermal growth factor (EGF) promotes hepatocyte growth and is bound in the liver by specific receptors. We have determined hepatic uptake of EGF in intact rats after an intravenous or intraportal injection of a bolus of 125I-labeled EGF. Ninety-nine percent of the intraportal dose was taken up by the liver in 3 min, whereas only 58% of the intravenous dose appeared in the liver in 10 min. Uptake was inhibited by simultaneous treatment with an excess of unlabeled EGF. At time zero, uptake appeared to be complete. Disappearance from the liver followed first-order kinetics. Within 90 min of an intraportal injection, an average of 19% of the injected radioisotope appeared in bile, of which approximately one-fifth was shown to be immunoprecipitable with a specific anti-EGF antiserum. Light microscopic autoradiography demonstrated a very steep portal-to-central lobular concentration gradient consistent with a high-capacity uptake system. After intraportal injection or after incubation with cultured hepatocytes, labeled EGF was shown to be bound to its hepatic receptors. The main receptor-ligand complex had a Mr of approximately equal to 160,000-170,000, determined by NaDodSO4/polyacrylamide gel electrophoresis.