Clearance of tissue plasminogen activator by mannose and galactose receptors in the liver

Abstract

The mechanism of uptake of radio-iodinated tissue plasminogen activator (125I-t-PA) was studied in rats. When trace amounts of 125I-t-PA were injected alone, the clearance followed a biphasic pattern in which 65% and 35% were cleared with alpha- and beta-kinetics (t1/2 (alpha) = 0.6 min, and t1/2 (beta) = 6.4 min), respectively. Co-injection with excess unlabelled t-PA or mannan changed the uptake kinetics to the monophasic beta-elimination pattern. Mannosylated albumin and ovalbumin, both of which bind to the hepatic mannose receptor, reduced the proportion of t-PA cleared with t1/2 (alpha) to 48% and 21%, respectively. A corresponding increase in the beta-elimination of t-PA was observed. The t1/2 (alpha) and t1/2 (beta) were unchanged. Studies on the clearance of 125I-ovalbumin also showed a biphasic elimination with an initial rapid phase, t1/2 (alpha), accounting for only 39% of the clearance of ovalbumin, as compared to 65% in the case of t-PA. Macromolecules with affinity for the galactose-receptor only, such as asialofetuin, or galactosylated albumin, did not significantly affect the clearance kinetics at the concentrations used. Asialoorosomucoid, which also carries galactosyl residues in the terminal position, reduced somewhat (from 65% to 48%) the proportion cleared with alpha-kinetics. Very high concentrations of galactose and N-acetyl-galactosamine, which are also known to compete for binding to the galactose receptor, lowered the proportion of t-PA cleared in the late beta-phase (reduced from 35% to 26% with galactose and to 19% with N-acetyl-galactosamine).(ABSTRACT TRUNCATED AT 250 WORDS)