PMID: 8611154Feb 1, 1996Paper

Interaction of mutants of tissue-type plasminogen activator with liver cells: effect of domain deletions

The Biochemical Journal
J KuiperT J van Berkel

Abstract

The fibrin-specific thrombolyticum tissue-type plasminogen activator (t-PA) has proven to be a potent drug in several clinical trials, but its clinical application is complicated by the rapid clearance of t-PA from the circulation. The rapid plasma clearance of t-PA results from the uptake of t-PA in the liver. t-PA consists of several domains which may be involved in the interaction with the liver. Three domain-deletion mutants, which were produced by the use of a cassette gene system, were studied in vivo and in vitro for their capacity to bind to the various types of rat liver cells. The three mutants lacked, in comparison to control t-PA, the epidermal growth factor (G) domain, the finger (F) domain or the G domain plus the first kringle (K1). The plasma clearance of the three mutants was slower than that of control t-PA. The slower plasma clearance resulted from a decreased liver uptake: 50 and 80% for t-PA mutants and control t-PA respectively. It was found that the K1 domain was of major importance for the uptake of t-PA by liver endothelial cells in vivo and in vitro. The high-affinity binding of t-PA (and t-PA mutants) to parenchymal liver cells depended largely on the presence of the G domain. Other domain(s), like th...Continue Reading

Citations

Nov 15, 2014·Stroke; a Journal of Cerebral Circulation·Fabian DocagneDenis Vivien
Apr 14, 2015·Jundishapur Journal of Natural Pharmaceutical Products·Fatemeh ShafieeHamid Mir Mohammad Sadeghi
Nov 4, 2015·Frontiers in Cellular Neuroscience·Arnaud ChevilleyDenis Vivien
Mar 16, 2000·International Journal of Experimental Pathology·K A StuartG G Skouteris
May 1, 2001·Nature Biotechnology·J A Kolkman, W P Stemmer
Oct 5, 2010·Journal of Biomedicine & Biotechnology·Fatemeh DavamiFereidoun Mahboudi
Jul 11, 2012·The Journal of Pharmacy and Pharmacology·Martin Flemmig, Matthias F Melzig
Dec 21, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kazumi KomoriyaYuichi Sugiyama
Feb 19, 2021·Journal of Stroke·Dmitri NikitinDong-Eog Kim

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