Effects of diethylnitrosamine on hepatic receptor binding and autophosphorylation of epidermal growth factor and insulin in rats

Abstract

Carcinogen-mediated alterations in hepatic membrane growth factor receptor activity were investigated with the use of the hepatocarcinogen diethylnitrosamine [(DENA) CAS: 55-18-5]. For the separate assessment of carcinogen-induced acute membrane receptor changes from changes associated with carcinogen-mediated alterations in growth, the receptor activity was measured both acutely after, and several months after, a single ip dose of DENA in male F344 rats. An acute dose-dependent decrease was observed in ligand binding and autophosphorylation of the epidermal growth factor (EGF) and insulin receptor. Binding decreased sharply by 36 hours and recovered by 30 days in Golgi fractions and more slowly in plasma membranes. Scatchard analysis revealed a decrease in receptor number but not affinity. Chronic DENA administration also decreased insulin and EGF binding. Hepatocellular carcinomas, induced by single DENA injections 1 year previously, had decreased EGF receptor binding and autophosphorylation compared to those seen in age-matched controls and also less extensive insulin receptor changes. Single DENA doses thus have two effects: an acute reversible receptor change and a delayed, apparently permanent change associated with altered growth.