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 p lay 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 TC DD on the activity of PEPCK in liver and two other tissues with high s pecific activity, viz. kidney and brown adipose tissue (BAT). Liver PE PCK activity was significantly decreased from 1 to 32 days after dosin g (60 mu g/kg). A clear dose response was present 8 days after dosing, beginning at a dose of 1 mu g/kg. In contrast to liver, TCDD treatmen t increased PEPCK activity in kidney and BAT, but only at the two high est doses administered (30 and 60 mu g/kg). PEPCK activity in kidney b egan to increase slowly, reaching a maximum on Day 16 and declining th ereafter, whereas in BAT the activity was significantly increased alre ady on Day 1 and maximally on Day 4 after dosing, A likely explanation for these tissue-specific effects is in part related to toxicokinetic s and in part to homeostatic responses of the organism to the toxic in sult of TCDD. High concentrations of TCDD in liver and BAT combined wi th early responses (1 day after dosing) suggest a direct effect in the se organs/tissues, whereas very low concentration and delayed response in kidney indicate an indirect effect. This interesting enzymatic con stellation suggests that the reduction in gluconeogenesis due to decre ased PEPCK activity in liver is partially counterbalanced by increased gluconeogenesis in kidney as a result of induction of PEPCK in this o rgan. Induction of PEPCK in BAT, where it is a glyceroneogenic enzyme, provides for the first time a plausible explanation for the initial a ccumulation of fat in BAT of TCDD-treated rats. (C) 1995 Academic Pres s, Inc.