Changes in the binding capacity of hepatic membranes for epidermal growth factor during multistage...

To study changes in hepatic capacity for binding epidermal growth factor (EGF) during 2-acetylaminofluorene (2-AAF)-induced, multistage hepatocarcinogenesis, a 5 cycle protocol of discontinuous 2-AAF administration was used to produce hepatocarcinogenesis in rats. The hallmark of the 5 cycle protocol is that rats fed 1 to 3 cycles of 2-AAF are at low risk for cancer, while rats fed 2-AAF for 4 or 5 cycles are at high risk for cancer. EGF binding by liver membranes was found to be lowered to 20-25% of control throughout the 5 cycle regimen. When the persistence of lowered EGF binding was tested by returning rats fed 2-AAF for 1 to 3 cycles to diet without 2-AAF for 3 weeks, binding was found to recover to 80 to 90% of values for control rats. In contrast, for rats fed 2-AAF for 4 or 5 cycles, EGF binding capacity remained low, 30 to 40% of control, following placement of rats on diet without 2-AAF for 3 weeks. Immunochemical analysis indicated a close correspondence between changes in EGF receptor levels and changes in the above EGF binding levels. These studies show that during the 2-AAF protocol, the 2-AAF-mediated loss in hepatic EGF binding capacity and EGF receptor protein undergo a transition from a reversible loss to a persistent loss in binding capacity, and EGF receptor protein, as rats underwent a change from low to high risk for developing hepatocarcinomas. The persistent decrease in hepatic EGF binding level may be associated with the progression stage of hepatocarcinogenesis.