Different receptors mediate the hepatic catabolism of tissue-type plasminogen activator and urokinase.
Tissue-type plasminogen activator (t-PA) and urokinase (u-PA) are proteins with partial structural similarity and which are of importance in the therapy of thrombotic diseases. Both are known to be cleared from the circulation in vivo by uptake in the liver. The present study investigated whether the hepatic catabolism of u-PA and t-PA is mediated by a common receptor system. Four experimental protocols of increasing complexity were used: hepatocyte plasma membranes, isolated primary hepatocytes, liver perfusion and whole animals. For t-PA, a specific high-affinity binding site to hepatocytes and plasma membranes could be defined with a mean Kd of 4 +/- 3 nM, whereas the Kd for u-PA was less than 300 nM. Binding of t-PA could not be competed for by u-PA, and vice versa. Furthermore, clearance of t-PA in isolated perfused rat livers and in rabbits in vivo was 3-fold higher than that of u-PA, and a 50-100-fold molar excess of u-PA failed to inhibit clearance of t-PA in either system, and vice versa. Taken together, the results imply that hepatic elimination of t-PA and u-PA is mediated by distinct receptor systems of differing affinity.
Krause
J
J
Department of Research, Dr. Karl Thomae G.m.b.H., Biberach/Riss, Federal Republic of Germany.
Seydel
W
W
Heinzel
G
G
Tanswell
P
P
D000818:Animals; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D009844:Oligosaccharides / Q000378:metabolism; D010960:Plasminogen Activators / Q000378:metabolism*; D051381:Rats; D011956:Receptors, Cell Surface / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D009844:Oligosaccharides; C524900:Plaur protein, rat; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator