Tissue-specific effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on the activity of phosphoenolpyruvate carboxykinase (PEPCK) in rats.
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.
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
M
M
Viluksela
B U
BU
Stahl
K K
KK
Rozman
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000201:enzymology*; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009928:Organ Specificity; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D000072317:Polychlorinated Dibenzodioxins; D010729:Phosphoenolpyruvate Carboxykinase (GTP)