AJP - Cell Physiology, Vol 258, Issue 4 C593-C598, Copyright © 1990 by American Physiological Society
Kinetic analysis of the downregulation of epidermal growth factor receptors in rats in vivo
S. Yanai, Y. Sugiyama, T. Iga, T. Fuwa and M. Hanano
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
We previously clarified the specific binding sites for epidermal growth
factor (EGF) in several organs in rats based on in vivo kinetic analysis
(D. C. Kim, Y. Sugiyama, H. Sato, T. Fuwa, T. Iga, and M. Hanano. J. Pharm.
Sci. 77: 200-207, 1988). In the present study, we have determined the
extent of the receptor downregulation and the recovery rate of the
available receptors for EGF in several organs in vivo. At the specified
times (30 min-24 h) after intravenous administration of excess unlabeled
EGF (300 micrograms/kg), the early-phase (less than 3 min) uptake
clearances (k1) of the tracer amount of 125I-EGF, which are proportional to
the cell-surface available receptor densities, were determined in the
liver, kidney, duodenum, jejunum, ileum, stomach, and spleen. As the
result, the k1 value in each organ at 30 min after intravenous
administration of unlabeled EGF was lowered close to the
receptor-independent clearance value, indicating that the cell-surface
receptors were almost completely downregulated, and thereafter, the k1
value showed gradual recovery to the control level. Furthermore, the
recovery half-lives showed interorgan differences, namely the half-life (20
min) in the liver was much shorter than those (2-4.5 h) in other organs.
These results were considered to reflect the processes of the recycling of
internalized EGF receptors to the cell-surface or recruitment of new
receptors. It was concluded that the recovery rate of the downregulated
receptors in the liver, which is most responsible for the plasma clearance
of EGF, is much faster than those in other organs.
