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

被引:3
|
作者
Tuomisto, J
Sewall, CH
Unkila, M
Pohjanvirta, R
Clark, GC
Viluksela, M
Rozman, K
Lucier, GW
机构
[1] NATL INST ENVIRONM HLTH, BIOCHEM RISK ANAL LAB, RES TRIANGLE PK, NC 27709 USA
[2] UNIV KANSAS, MED CTR, DEPT PHARMACOL TOXICOL & THERAPEUT, KANSAS CITY, KS 66160 USA
关键词
dioxin; TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin); EGF (epidermal growth factor); EGF receptor; phosphoenolpyruvate carboxykinase (PEPCK); TCDD-resistant rat; TCDD-sensitive rat; strain difference; liver; rat;
D O I
10.1016/1382-6689(95)00016-X
中图分类号
X [环境科学、安全科学];
学科分类号
08 ; 0830 ;
摘要
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 mu g/kg), the downregulation was 80%. In the resistant H/W strain, two non-lethal doses were used (50 and 500 mu g/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 (CYP1Al induction) is similar. The results demonstrate that downregulation of the EGF receptor by TCDD is strain-dependent as well as dose- and time-dependent.
引用
收藏
页码:109 / 116
页数:8
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