Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Metabolism of the Intravenously Administered Recombinant Human Basic Fibroblast Growth Factor, Trafermin, in Liver and Kidney : Degradation Implicated in Its Selective Localization to the Fenestrated Type Microvasculatures
Takuro YUGEAkihiko FURUKAWAKatsuhiro NAKAMURAYutaka NAGASHIMAKohki SHINOZAKIToshiyuki NAKAMURARyohei KIMURA
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1997 Volume 20 Issue 7 Pages 786-793

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Abstract

The fate of trafermin (recombinant human basic fibroblast growth factor) was examined after intravenous administration of its iodinated form to rats. Autoradiography at 5 and 30 min after the injection showed that 125I-trafermin is localized specifically in the fenestrated endothelium through binding to heparan sulfate proteoglycans (HSPG) in liver, kidney, adrenal, spleen, hypophysis and bone marrow. Metabolites in the organs were examined at 5 min and 24 h after the injection. More than 73% of radioactivity in liver and kidney was extractable at either time point, and a large majority of the extracted radioactivity was heparin-binding. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) revealed that the substantial radioactivity recovered from liver and kidney can commonly be attributed to a peptide with the same molecular weight as the intact trafermin (B-1, 17.7 kDa) and only three truncated metabolites (B-2, 15.0 kDa; B-3, 7.2 kDa; B-4, 4.2 kDa). Because no truncated metabolites were found in serum, these metabolites seem to be produced inherently in liver and kidney. Although they all retained heparin-binding capacity, only B-1 and B-2 exhibited a stimulatory effect on proliferation of endothelial cells, and these bioactive peptides disappeared completely from liver within a day, indicating a rapid inactivation process in the organs. Taken together with the morphological evidence on autoradiography, it seems most likely that the injected trafermin could be inactivated in sinusoidal endothelial cells, probably through a well-known internalization mechanism of the basic fibroblast growth factor-HSPG complex.

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