Ligand-induced downregulation of receptor-mediated clearance of hepatocyte growth factor in rats.
The change in tissue uptake clearance of 125I-labeled hepatocyte growth factor (HGF) after an intravenous injection of an excess (120 micrograms/kg) of unlabeled HGF was examined in rats. The heparin-washable component of the hepatic uptake clearance of 125I-HGF was only slightly changed, whereas the heparin-resistant component was significantly reduced 30 min after injection of excess HGF, followed by gradual recovery with a half-life of 3.2 h. Because the former clearance mainly represents 125I-HGF association with heparan sulfate proteoglycan on the cell surface and/or extracellular matrix, whereas the latter includes relatively specific clearance, such as receptor-mediated endocytosis, this result suggests that injection of excess HGF selectively causes downregulation of receptor-mediated HGF clearance in the liver. Downregulation could also be observed for HGF receptor density in isolated liver plasma membrane, assessed by Western blot analysis by means of anti-receptor antibody, 30 min after injection of excess unlabeled HGF, supporting the hypothesis that the overall elimination of HGF from the systemic circulation can be affected by a change in HGF receptor density on the liver cell surface.
Liu
K X
KX
Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.
Kato
Y
Y
Kino
I
I
Nakamura
T
T
Sugiyama
Y
Y
D000818:Animals; D015536:Down-Regulation; D006207:Half-Life; D006493:Heparin / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D007700:Kinetics; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D007457:Iodine Radioisotopes; D008024:Ligands; D017228:Hepatocyte Growth Factor; D006493:Heparin; D019859:Proto-Oncogene Proteins c-met