CHANGES IN THE BINDING-CAPACITY OF HEPATIC MEMBRANES FOR EPIDERMAL GROWTH-FACTOR DURING MULTISTAGE HEPATOCARCINOGENESIS IN RATS

To study changes in hepatic capacity for binding epidermal growth fact or (EGF) during 2-acetylaminofluorene (2-AAF)-induced, multistage hepa tocarcinogenesis, a 5 cycle protocol of discontinuous 2-AAF administra tion 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 l ow 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 lower ed to 20-25% of control throughout the 5 cycle regimen. When the persi stence of lowered EGF binding was tested by returning rats fed 2-AAF f or 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 r ats 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 bi nding levels. These studies show that during the 2-AAF protocol, the 2 -AAF-mediated loss in hepatic EGF binding capacity and EGF receptor pr otein undergo a transition from a reversible loss to a persistent loss in binding capacity, and EGF receptor protein, as rats underwent a ch ange from low to high risk for developing hepatocarcinomas. The persis tent decrease in hepatic EGF binding level may be associated with the progression stage of hepatocarcinogenesis. (C) 1996 Academic Press, In c.