AMINO-ACID SUBSTITUTIONS ALTER THE TISSUE DISTRIBUTION OF MURINE INTERFERON-ALPHA-1

Novel analogs created by site-directed mutagenesis of murine interfero n-alpha1 (IFN-alpha1) were used to examine the effect of alterations i n structure and biological activity of murine IFN-alpha1 on tissue dis tribution in mice. The analogs were biosynthetically labeled with [S-3 5]methionine using a cell-free transcription-translation system and in jected intravenously into adult male BALB/c mice. Levels of murine IFN -alpha1 (dpm/gram wet weight) were highest in the liver, spleen, kidne y, 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-alpha1. In general, analogs with reduced antiviral acti vity showed reduced uptake by the spleen and lung. The amount in the k idney of the analog R33E, which has no detectable antiviral activity i n vitro, was substantially higher than that of native IFN, suggesting a greater rate of excretion of this analog. An analog of human IFN-alp ha4, which had increased antiviral activity on murine cells, showed in creased uptake in the liver, spleen, and lung. These findings, togethe r with the results of a previous study using autoradiography (johns et al., 1990, Cancer Res. 50, 4718-4723) indicate that nonspecific uptak e by parenchymal cells in the liver, spleen, and lung is unaffected by changes in antiviral activity, while specific, receptor-mediated loca lization of IFN in regions rich in macrophages is reduced in accordanc e with the reduction in antiviral activity.