Clearance of the heavy and light polypeptide chains of human tissue-type plasminogen activator in rats.
In order to assess which part of the tissue-type plasminogen activator (t-PA) molecule should be (genetically) modified to obtain more-slowly-clearing mutants, two-chain t-PA and its isolated heavy and light chains were radiolabelled and injected into rats. The vast majority of t-PA and the heavy chain disappeared from the blood circulation with half-lives of 2.3 and 1.0 min respectively. The clearance of the light chain was biphasic, owing to complex-formation with plasma proteinase inhibitors. The disappearance of di-isopropylphospho-light chain, which has a blocked active site, was nearly monophasic, with a half-life of 5.7 min. Organ distribution studies showed that hepatic clearance constituted the major pathway in all cases. These results strongly suggest that t-PA is recognized by the liver primarily through the heavy chain.
D000818:Animals; D001665:Binding Sites; D002850:Chromatography, Gel; D006207:Half-Life; D008297:Male; D010455:Peptides / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D010455:Peptides; D010959:Tissue Plasminogen Activator