Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on liver phosphoenolpyruvate carboxykinase (PEPCK) activity, glucose homeostasis and plasma amino acid concentrations in the most TCDD-susceptible and the most TCDD-resistant rat strains

Reduced gluconeogenesis due to decreased activity of key gluconeogenic enzy mes in liver, together with feed refusal, has been suggested to play an imp ortant rule in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)induced lethality in rats. This study was carried out to further analyse the toxicological si gnificance of reduced gluconeogenesis by comparing dose-responses and time- courses of effects of TCDD on the activity of phosphoenolpyruvate carboxyki nase (PEPCK) in liver, liver glycogen concentration as well as plasma conce ntrations of glucose and amino acids in both genders of TCDD-sensitive Long -Evans (L-E) rats and TCDD-resistant Han/Wistar (H/W) rats. A dose-dependen t decrease in PEPCK activity was observed in H/W rats, but in L-E rats the activity was not decreased. However, TCDD impaired the strong increase in l iver PEPCK activity observed in pair-fed controls of the L-E strain. Liver glycogen concentrations were severely decreased in L-E rats and moderately in H/W rats. This effect seems to be secondary to reduced feed intake, sinc e a similar decrease was seen in pair-fed controls. Decreases in plasma glu cose concentrations were also more profound in L-E rats than in H/W rats, b ut pair-fed controls were generally less affected. Circulating concentratio ns of amino acids were markedly increased in TCDD-treated L-E rats, which i s likely to reflect increased mobilization of amino acids and their decreas ed metabolism in liver. Reduction of liver PEPCK activity cannot account fo r the sensitivity difference of these two strains of rats in terms of morta lity. Nevertheless, the response of both strains of TCDD-treated rats regar ding gluconeogenesis is different from that seen in pair-fed controls and s uggesting that impairment of this pathway contributes to the development of the wasting syndrome.