Importance of the liver in plasma clearance of hepatocyte growth factors in rats.
After intravenous administration of 125I-labeled hepatocyte growth factor (HGF), trichloroacetic acid-precipitable radioactivity in the plasma disappeared rapidly with an early phase half-life of 4 min. The amounts of 125I-HGF distributed to the liver, adrenal, spleen, kidney, and lung tissues were much greater than those that could be accounted for by distribution to the extracellular space alone. The first-pass removal of 125I-HGF by the liver was approximately 26%; the liver accounted for approximately 70% of early-phase removal. The hepatic handling was also analyzed using a single-pass perfused liver system. The steady-state extraction ratio of tracer 125I-HGF was 0.48 but dropped to 0.23 in the presence of excess HGF (135 pM), demonstrating hepatic removal saturation of HGF. In the presence of excess HGF, the heparin-washable 125I-HGF, the heparin-resistant and acid-washable 125I-HGF, and the internalized 125I-HGF dropped to 54, 31, and 32% of the control values. The presence of at least two binding sites for HGF on the liver cell surfaces was made clear: the heparin-washable site and the heparin-resistant and acid-washable binding site, considered to have higher affinity for HGF. The internalization of 125I-HGF was observed to some extent even in the presence of excess HGF and phenylarsine oxide, known to be an inhibitor of polypeptides receptor-mediated endocytosis, suggesting the contribution of a relatively nonspecific internalization mechanism as well as receptor-mediated endocytosis.
Liu
K X
KX
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Kato
Y
Y
Narukawa
M
M
Kim
D C
DC
Hanano
M
M
Higuchi
O
O
Nakamura
T
T
Sugiyama
Y
Y
D000818:Animals; D001646:Bile / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000097:blood* / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D017228:Hepatocyte Growth Factor