D-mannose dimer introduced human recombinant interleukin- 1 alpha, NEO IL-1 alpha, exhibits altered tissue distribution in mice.
Previous studies have demonstrated that the carbohydrate-introduced recombinant human IL-l alpha exhibited impairment in both biologic activities in all the experiments in vitro and receptor binding capacity compared with intact IL-l alpha. However, the glycosylated IL-l alpha exhibited selective activities in vivo. In this study, we compared the tissue distribution of IL-l alpha and IL-l alpha coupled with D-Mana (l-6)Man [Man2 alpha) (l-6)IL-l alpha] in mice. Mice were injected by intravenous and intraperitoneal routes with 2.0 mu g radiolabeled IL-l alpha. At 1 and 2 h after IP injection, the level of Man2 alpha) (l-6)IL-l alpha decreased twofold compared with that of IL-l alpha in kidney. In contrast, at 1 hour after administration, Man2 alpha) (l-6)IL-l alpha exhibited higher levels than IL-l alpha in blood, heart, and liver. No significant difference was observed in brain at each time point. IV injection demonstrated that Man2 alpha)(l-6)IL-l alpha decreased to approximately one-half the level of rhIL-l alpha in kidney. In contrast, Man(2 alpha) (l-6)IL-l alpha increased twofold over that of IL-l alpha in liver at 1 h after dosing. These findings are consistent with the result of IP injection. There was no significant difference between IL-l alpha and glycosylated IL-l alpha at 4 h after IV administration. These differences in tissue distribution may contribute to the selective activities of glycosylated IL-l alpha in vivo. The results also suggest that by coupling with mannose dimer, it is possible to develop neocytokines prone to liver distribution.
Takei
Y
Y
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Nagoya City University, Tanabe-3, Mizuho-Ku Nagoya 467, Japan.
Chiba
T
T
Nabeshima
S
S
Naruoka
M
M
Wada
K
K
Onozaki
K
K
D000818:Animals; D002700:Chloramines; D006031:Glycosylation; D006801:Humans; D007202:Indicators and Reagents; D007375:Interleukin-1 / Q000378:metabolism / Q000493:pharmacokinetics; D008362:Mannosides / Q000378:metabolism / Q000493:pharmacokinetics*; D051379:Mice; D008813:Mice, Inbred ICR; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014105:Tosyl Compounds
D002700:Chloramines; D007202:Indicators and Reagents; D007375:Interleukin-1; D008362:Mannosides; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D014105:Tosyl Compounds; C016300:chloramine-T