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 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.
Noble Center for Biomedical Research, Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.
L A
LA
DeCicco
P L
PL
Panzeter
R E
RE
Cashman
D P
DP
Ringer
D015073:2-Acetylaminofluorene / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D004815:Epidermal Growth Factor; D015073:2-Acetylaminofluorene; D066246:ErbB Receptors