Amino acid substitutions alter the tissue distribution of murine interferon-alpha 1.
Novel analogs created by site-directed mutagenesis of murine interferon-alpha 1 (IFN-alpha 1) were used to examine the effect of alterations in structure and biological activity of murine IFN-alpha 1 on tissue distribution in mice. The analogs were biosynthetically labeled with [35S]methionine using a cell-free transcription-translation system and injected intravenously into adult male BALB/c mice. Levels of murine IFN-alpha 1 (dpm/gram wet weight) were highest in the liver, spleen, kidney, and lung, lower in the heart, and quite low in testis, brain, skin, and muscle. The tissue distribution of the analogs differed from that of murine IFN-alpha 1. In general, analogs with reduced antiviral activity showed reduced uptake by the spleen and lung. The amount in the kidney of the analog R33E, which has no detectable antiviral activity in vitro, was substantially higher than that of native IFN, suggesting a greater rate of excretion of this analog. An analog of human IFN-alpha 4, which had increased antiviral activity on murine cells, showed increased uptake in the liver, spleen, and lung. These findings, together with the results of a previous study using autoradiography (Johns et al., 1990, Cancer Res. 50, 4718-4723) indicate that nonspecific uptake by parenchymal cells in the liver, spleen, and lung is unaffected by changes in antiviral activity, while specific, receptor-mediated localization of IFN in regions rich in macrophages is reduced in accordance with the reduction in antiviral activity.
Department of Biochemistry, Monash University, Clayton, Victoria, Australia.
J A
JA
Kerry
T G
TG
Johns
A W
AW
Linnane
B F
BF
Cheetham
D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D006801:Humans; D007275:Injections, Intravenous; D016898:Interferon-alpha / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016297:Mutagenesis, Site-Directed; D013329:Structure-Activity Relationship; D014018:Tissue Distribution / Q000502:physiology
D000596:Amino Acids; D016898:Interferon-alpha