Catabolic Pathways for Streptokinase, Plasmin, and Streptokinase Activator Complex in Mice

Abstract

The catabolic pathways of streptokinase, plasmin, and activator complex prepared with human plasminogen were studied in mice. ¹²⁵I-streptokinase clearance occurred in the liver and was 50% complete in 15 min. Incubation with mouse plasma had no effect on the streptokinase clearance rate. Complexes of plasmin and α₂-plasmin inhibitor were eliminated from the plasma by a specific and saturable pathway. Competition experiments demonstrated that this pathway is responsible for the clearance of injected plasmin. Streptokinase-plasminogen activator complex formed with either ¹²⁵I-plasminogen or ¹²⁵I-streptokinase cleared in the liver at a significantly faster rate than either of the uncomplexed proteins (50% clearance in p-Nitrophenyl-p′-guanidinobenzoate-HCl or pancreatic trypsin inhibitor-treated complex cleared slowly compared with untreated complex independent of which protein was radiolabeled. Significant competition for clearance was demonstrated between α₂-macroglobulin-trypsin and activator complex only when the plasmin(ogen) was the radiolabeled moiety. Large molar excesses of α₂-plasmin inhibitor-plasmin failed to retard the clearance of activator complex. Hepatic binding of streptokinase-plasmin, in liver perfusion experiments, was dependent upon prior incubation with plasma (8-10% uptake compared to a background of ∼ 2.5%). Substitution of human α₂-macroglobulin for plasma also resulted in binding when the incubation was performed for 10 min at 37°C (7.5%). Electrophoresis experiments confirmed the transfer of 0.8 mol plasmin/mol α₂-macroglobulin when activator complex was incubated at 37°C with α₂-macroglobulin for 40 min. Streptokinase transfer from activator complex to α₂-macroglobulin was negligible. The in vivo clearance of activator complex is proposed to involve active attack of the complex on the α₂-macroglobulin “bait region,” resulting in facilitated plasmin transfer. Dissociated streptokinase is rapidly bound and cleared by sites in the liver.