The role of the liver in clearance of glycoproteins from the general circulation, with special reference to intestinal alkaline phosphatase

Abstract

Glycoproteins represent a wide variety of macromolecules with important physiological functions. Characteristic variations in carbohydrate composition and plasma concentration of these proteins may occur during pathological conditions. Steady-state plasma concentrations are determined by release from normal or diseased tissues and simultaneous clearance from the general circulation. The liver occupies a central position in the production but also clearance and catabolism of such glycoproteins. A number of specialized receptor-mediated transport processes for different types of glycoproteins in this organ is reviewed. Membrane recognition is generally followed by absorptive endocytosis and vesicle transport to lysosomes, Golgi system and/or bile canaliculis. The charge of the protein, the nature of the terminal sugar residue or complex formation with other glycoproteins may determine the extent of uptake in the various cell types of the liver. By means of these transport processes the liver is able to remove potentially dangerous macromolecules such as denatured proteins, aggressive enzymes and immunocomplexes from the general circulation. Drugs can bind to some of these proteins or may interact with the hepatic transport or catabolism processes. Special attention is paid to the hepatic clearance of asialoglycoproteins with terminal galactose groups. Intestinal alkaline phosphatase is used as a model compound to characterize the pharmacokinetic profiles of hepatic uptake and biliary excretion in the rat in vivo and isolated perfused rat livers. Histochemical and electron-microscopic studies demonstrated a galactose-specific, receptor-mediated endocytotic process, mainly but not exclusively localized in centrolobular hepatocytes. Drug interactions with these processes will be the subject of further investigations.