O-glycosylation delays the clearance of human IGF-binding protein-6 from the circulation.
OBJECTIVE
The actions of insulin-like growth factors (IGF-I and IGF-II) are modulated by a family of six structurally related, high-affinity binding proteins (IGFBPs 1-6). IGFBP-6, an O-linked glycoprotein, preferentially binds IGF-II and inhibits its actions. The aim of this study was to investigate whether O-glycosylation modulates the pharmacokinetics of IGFBP-6.


METHODS
The pharmacokinetic profiles of (125)I-labelled glycosylated (g) and non-glycosylated (n-g) recombinant human IGFBP-6 were studied following intravenous bolus administration in anaesthetised rats.


RESULTS
The redistribution half-life of gIGFBP-6 was 2.3-fold greater than that of n-gIGFBP-6 (14.4+/- 1.2 vs 6.3+/-1.5 min, P=0. 006). The elimination half-life of gIGFBP-6 was 21-fold greater than that of n-gIGFBP-6 (584.2+/-130.2 vs 28.0+/-4.2 min, P=0.019). The effect of O-glycosylation on IGFBP-6 pharmacokinetics was not due to inhibition of intravascular proteolysis. Radioactivity was found in stomach, kidneys, lung, spleen, heart and liver but not brain 4h after injection of g or n-gIGFBP-6.


CONCLUSIONS
O-glycosylation delays the clearance of IGFBP-6 from the circulation and may therefore contribute to its role as a circulating inhibitor of IGF-II actions.
Marinaro
J A
JA
Department of Medicine, Austin and Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria 3084, Australia.
Casley
D J
DJ
Bach
L A
LA
D000818:Animals; D006031:Glycosylation; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution
D018976:Insulin-Like Growth Factor Binding Protein 6; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins