Existence of two nonlinear elimination mechanisms for hepatocyte
growth factor in rats.
Liu, Ke-Xin, Yukio Kato, Motohiro Kato, Tai-Ichi Kaku, Toshikazu
Nakamura, and Yuichi Sugiyama.
Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113, Bioproducts Industry Co., Ltd., Tomigaya,
Shibuya-ku, Tokyo 151, and Biomedical Research Center, Osaka
University School of Medicine, Suita, Osaka 565, Japan
APStracts 4:0154E, 1997.
Nonlinearity in the overall elimination of hepatocyte growth factor
(HGF) was examined in rats. After i.v. administration, the plasma
clearance (CLplasma) of HGF exhibited a dose-dependent biphasic
reduction with high- and low-affinity components. Considering our
previous finding that both receptor-mediated endocytosis (RME) and a
low-affinity uptake mechanism, probably mediated by heparan sulfate
proteoglycan (HSPG), in the liver are major HGF clearance mechanisms,
it may be that saturation of CLplasma at lower and higher doses
represents saturation of RME and HSPG-mediated uptake, respectively.
At an HGF dose (1.46 nmol/kg) which completely saturates the high
affinity component, CLplasma was almost completely reduced when HGF
was premixed with heparin. However, CLplasma was reduced by heparin
to, at most, 1/5 that after HGF alone in a dose near the linear range
(3.66 pmol/kg). Saturation of CLplasma for HGF premixed with heparin
was monophasic, and nonlinear only at the lowest HGF doses. In vitro,
high-affinity binding of 35S-heparin to HGF was found showing that
one HGF molecule binds to the penta- or hexasaccharide unit. Since
mitogenic activity of HGF has been reported in the presence of
heparin, these results suggest that heparin mainly inhibits low
-affinity HGF uptake by complexing with HGF while its effect on RME is
relatively minor.
Received 24 February 1997; accepted in final form 7 July 1997.
APS Manuscript Number E0084-7.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 24 July 1997