Differences in binding of epidermal growth factor to liver membranes of TCDD-resistant and TCDD-sensitive rats after...

Epidermal growth factor (EGF) receptor has been implied as having a role in certain actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). After a single dose of TCDD, the receptor has been shown to be downregulated in several tissues including the liver. Two rat substrains, the Han/Wistar (Kuopio; H/W) rat and the Long-Evans (Turku AB; L-E) rat exhibit over a 1000-fold difference in their sensitivity to the lethal effect of TCDD. This large sensitivity difference was utilized in the current study to investigate whether or not a correlation exists between TCDD lethality and biochemical endpoints related to the hepatic EGF receptor. In the TCDD-sensitive L-E strain both the B(max) of the EGF receptor and the receptor protein as measured by Western blots, decreased dose and time dependently. Ten days after a lethal dose of TCDD (50 μg/kg), the downregulation was 80%. In the resistant H/W strain, two non-lethal doses were used (50 and 500 μg/kg), since the lethal dose is not known. These doses caused a downregulation already at 4 days after dosing, but no further decrease by day 10. The activity of phosphoenolpyruvate carboxykinase (PEPCK, the main gluconeogenetic enzyme in the liver and a proposed target of TCDD) decreased in H/W rats at least to the same extent as in L-E rats at both 4 and 10 days. It is concluded that EGF receptor downregulation is different in the two rat strains studied, despite the fact that a classical Ah receptor-regulated response (CYP1A1 induction) is similar. The results demonstrate that downregulation of the EGF receptor by TCDD is strain-dependent as well as dose- and time-dependent.