In vivo and in vitro interaction of high and low molecular weight single-chain urokinase-type plasminogen activator with rat liver cells.
The plasma clearance and the interaction of high (HMW) and low (LMW) molecular weight single-chain urokinase-type plasminogen activator (scu-PA) with rat liver cells was determined. 125I-Labeled HMW- and LMW-scu-PA were rapidly cleared from plasma with a half-life of 0.45 min and a maximal liver uptake of 55% of the injected dose. Liver uptake of scu-PA was mediated by parenchymal cells. Excess of unlabeled HMW-scu-PA reduced the liver uptake of 125I-HMW-scu-PA strongly. In vivo liver degradation of scu-PA was reduced by inhibitors of the lysosomal pathway. A high affinity binding site (Kd 45 nM, Bmax 1.7 pmol/mg cell protein) for both HMW- and LMW-scu-PA was determined on isolated parenchymal liver cells. Cross-competition binding studies showed that LMW- and HMW-scu-PA bind to the same site. Tissue-type plasminogen activator, mannose- or galactose-terminated glycoproteins did not affect the scu-PA binding to parenchymal liver cells. It is concluded that LMW- and HMW-scu-PA are taken up in the liver by a common, newly identified recognition site on parenchymal liver cells and are subsequently degraded in the lysosomes. It is suggested that this site is important for the regulation of the turnover of scu-PA.
Kuiper
J
J
Division of Biopharmaceutics, Sylvius Laboratory, University of Leiden, The Netherlands.
Rijken
D C
DC
de Munk
G A
GA
van Berkel
T J
TJ
D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D006801:Humans; D007457:Iodine Radioisotopes; D007527:Isoenzymes / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008970:Molecular Weight; D011865:Radioisotope Dilution Technique; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D014568:Urokinase-Type Plasminogen Activator / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics
D007457:Iodine Radioisotopes; D007527:Isoenzymes; D014568:Urokinase-Type Plasminogen Activator