Weber L W, Lebofsky M, Stahl B U, Gorski J R, Muzi G, Rozman K
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66103.
Toxicology. 1991 Feb;66(2):133-44. doi: 10.1016/0300-483x(91)90214-l.
Male Sprague--Dawley rats (350-375 g) were injected i.p. with TCDD (25 [sublethal dose] and 125 micrograms/kg [lethal dose], respectively, in corn oil/acetone), or vehicle only; vehicle-treated animals were pair-fed to their TCDD-treated counterparts. 1, 2, 4, 8, 16, and 32 days (28 days for lethal dose) thereafter, animals were sacrificed and activities of two key enzymes of gluconeogenesis determined in livers of rats. In livers of pair-fed rats both enzyme activities were little affected. In the livers of TCDD-treated animals the activity of phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) decreased rapidly, exhibiting significant losses by the 2nd day after treatment. Time course and extent of loss of PEPCK activity (about 50%) were similar after either dose. The activity of glucose-6-phosphatase (G-6-Pase, EC 3.1.3.9) decreased more slowly as a result of TCDD treatment; statistically significant losses were observed by 4 or 8 days after the lethal and sublethal dose, respectively. These results confirm the hypothesis that reduced in vivo rates of gluconeogenesis in TCDD-treated rats are due to decreased activities of gluconeogenic enzymes. In an additional set of experiments, rats were treated with 125 micrograms/kg TCDD, 25 micrograms/kg TCDD, or with vehicle alone. The 25 micrograms/kg or vehicle-treated rats were then pair-fed to rats dosed with 125 micrograms/kg of TCDD. Mean time to death and body weight loss at the time of death were essentially identical in all groups, lending additional support to the hypothesis that reduced feed intake is the major cause of TCDD-induced death in male Sprague--Dawley rats. Both appetite suppression and reduced total PEPCK activity in whole livers occurred in the same dose-ranges of TCDD, suggesting the possibility of a cause-effect relationship.
将雄性斯普拉格-道利大鼠（体重350 - 375克）腹腔注射四氯二苯并对二噁英（分别以25微克/千克[亚致死剂量]和125微克/千克[致死剂量]溶于玉米油/丙酮中），或仅注射溶媒；对接受溶媒处理的动物进行配对喂食，使其食量与接受四氯二苯并对二噁英处理的对应动物相同。此后1、2、4、8、16和32天（致死剂量组为28天），处死动物并测定大鼠肝脏中糖异生的两种关键酶的活性。在配对喂食的大鼠肝脏中，两种酶的活性几乎未受影响。在接受四氯二苯并对二噁英处理的动物肝脏中，磷酸烯醇式丙酮酸羧激酶（PEPCK，EC 4.1.1.32）的活性迅速下降，在处理后第2天就出现显著降低。两种剂量处理后，PEPCK活性下降的时间进程和幅度（约50%）相似。由于四氯二苯并对二噁英处理，葡萄糖-6-磷酸酶（G-6-Pase，EC 3.1.3.9）的活性下降较慢；分别在致死剂量和亚致死剂量处理后4天和8天观察到统计学上的显著降低。这些结果证实了以下假设：四氯二苯并对二噁英处理的大鼠体内糖异生速率降低是由于糖异生酶活性降低所致。在另一组实验中，大鼠分别接受125微克/千克四氯二苯并对二噁英、25微克/千克四氯二苯并对二噁英或仅接受溶媒处理。然后将25微克/千克或接受溶媒处理的大鼠与接受125微克/千克四氯二苯并对二噁英处理的大鼠进行配对喂食。所有组的平均死亡时间和死亡时的体重减轻基本相同，这进一步支持了以下假设：摄食量减少是四氯二苯并对二噁英诱导雄性斯普拉格-道利大鼠死亡的主要原因。在相同的四氯二苯并对二噁英剂量范围内，既出现了食欲抑制，又出现了全肝总PEPCK活性降低，这表明可能存在因果关系。
