Viluksela M, Stahl B U, Rozman K K
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Toxicol Appl Pharmacol. 1995 Dec;135(2):308-15. doi: 10.1006/taap.1995.1237.
Reduced gluconeogenesis due to decreased activity of key gluconeogenic enzymes in liver, together with feed refusal, has been suggested to play an important role in TCDD-induced lethality in rats. In this study the toxicological significance of reduced gluconeogenesis was further analyzed by studying dose responses and time courses of effects of TCDD on the activity of PEPCK in liver and two other tissues with high specific activity, viz. kidney and brown adipose tissue (BAT). Liver PEPCK activity was significantly decreased from 1 to 32 days after dosing (60 micrograms/kg). A clear dose response was present 8 days after dosing, beginning at a dose of 1 microgram/kg. In contrast to liver, TCDD treatment increased PEPCK activity in kidney and BAT, but only at the two highest doses administered (30 and 60 micrograms/kg). PEPCK activity in kidney began to increase slowly, reaching a maximum on Day 16 and declining thereafter, whereas in BAT the activity was significantly increased already on Day 1 and maximally on Day 4 after dosing. A likely explanation for these tissue-specific effects is in part related to toxicokinetics and in part to homeostatic responses of the organism to the toxic insult of TCDD. High concentrations of TCDD in liver and BAT combined with early responses (1 day after dosing) suggest a direct effect in these organs/tissues, whereas very low concentration and delayed response in kidney indicate an indirect effect. This interesting enzymatic constellation suggests that the reduction in gluconeogenesis due to decreased PEPCK activity in liver is partially counterbalanced by increased gluconeogenesis in kidney as a result of induction of PEPCK in this organ. Induction of PEPCK in BAT, where it is a glyceroneogenic enzyme, provides for the first time a plausible explanation for the initial accumulation of fat in BAT of TCDD-treated rats.
肝脏中关键糖异生酶活性降低导致糖异生减少，再加上拒食，被认为在TCDD诱导的大鼠致死性中起重要作用。在本研究中，通过研究TCDD对肝脏、肾脏和棕色脂肪组织（BAT）这两个具有高比活性的其他组织中磷酸烯醇式丙酮酸羧激酶（PEPCK）活性的剂量反应和效应时间进程，进一步分析了糖异生减少的毒理学意义。给药（60微克/千克）后1至32天，肝脏PEPCK活性显著降低。给药8天后出现明显的剂量反应，起始剂量为1微克/千克。与肝脏相反，TCDD处理增加了肾脏和BAT中的PEPCK活性，但仅在给予的两个最高剂量（30和60微克/千克）时出现。肾脏中的PEPCK活性开始缓慢增加，在第16天达到最大值，此后下降，而在BAT中，给药后第1天活性就显著增加，在第4天达到最大值。这些组织特异性效应的一个可能解释部分与毒代动力学有关，部分与机体对TCDD毒性损伤的稳态反应有关。肝脏和BAT中高浓度的TCDD以及早期反应（给药后1天）表明在这些器官/组织中有直接作用，而肾脏中极低浓度和延迟反应表明是间接作用。这种有趣的酶学情况表明，肝脏中由于PEPCK活性降低导致的糖异生减少，部分被肾脏中由于该器官中PEPCK诱导而增加的糖异生所抵消。BAT中PEPCK的诱导，在BAT中它是一种甘油生成酶，首次为TCDD处理的大鼠BAT中脂肪的初始积累提供了一个合理的解释。
