J. Kuiper et al., INTERACTION OF MUTANTS OF TISSUE-TYPE PLASMINOGEN-ACTIVATOR WITH LIVER-CELLS - EFFECT OF DOMAIN DELETIONS, Biochemical journal, 313, 1996, pp. 775-780
The fibrin-specific thrombolyticum tissue-type plasminogen activator (
t-PA) has proven to be a potent drug in several clinical trials, but i
ts 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 whic
h may be involved in the interaction with the liver. Three domain-dele
tion 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 compari
son to control t-PA, the epidermal growth factor (G) domain, the finge
r (F) domain or the G domain plus the first kringle (K-1). The plasma
clearance of the three mutants was slower than that of control t-PA. T
he slower plasma clearance resulted from a decreased liver uptake: 50
and 80% for t-PA mutants and control t-PA respectively. It was found t
hat the K-1 domain was of major importance for the uptake of t-PA by l
iver endothelial cells in vivo and in vitro. The high-affinity binding
of t-PA (and t-PA mutants) to parenchymal liver cells depended largel
y on the presence of the G domain. Other domain(s), like the F, K-2 or
protease domain, may be responsible for low-affinity, t-PA-specific b
inding to rat parenchymal liver cells.