Zonal differences of DNA synthesis in hepatocytes induced by hepatocyte growth factor and/or scatter factor (HGF/SF) and epidermal growth factor (EGF) were investigated using male Wistar rats under fed or starved conditions. Overall, DNA synthesis was greater in fed rats than in starved rats. The predominance of EGF in periportal hepatocytes (PPH) on zonal DNA synthesis was reversed by starved conditions, but the predominance of HGF/SF on zonal DNA synthesis in perivenous hepatocytes (PVH) was not influenced by nutritional conditions. ¹²⁵I-labeled EGF and ¹²⁵I-labeled HGF/SF-receptor binding studies revealed no significant difference between PPH and PVH in starved or fed rats. To investigate the mechanism of the signal transduction pathway, we used genistein, an inhibitor of tyrosine kinase. Genistein had different effects on zonal difference in EGF and HGF/SF. In EGF, 1 µg/ml genistein abolished zonal differences, but in HGF/SF 1 µg/ml genistein did not abolish zonal differences. These data suggest that, in contrast to HGF/SF, zonal difference of DNA synthesis by EGF was dependent on nutritional conditions and DNA synthesis induced by HGF/SF and EGF might be related to tyrosine kinase, but the influence of tyrosine kinase on DNA synthesis was different between HGF/SF and EGF.