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  • 1
    ISSN: 1432-0738
    Schlagwort(e): 2,3,7,8-Tetrachlorodibenzo-p-dioxin ; Dose-response ; Gluconeogenesis ; Phosphoenolpyruvate carboxykinase ; Pyruvate kinase ; Pyruvate carboxylase ; Glucose-6-phosphatase
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Male Sprague-Dawley rats (240–245 g) were dosed ip with 5, 15, 25, or 125 μg/kg -,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in corn oil. Ad libitumfed and pair-fed controls received vehicle (4 ml/kg) alone. Two or 8 days after dosing five rats of each group were sacrificed, their livers removed and assayed for the activities of three gluconeogenic enzymes [phosphoenol-pyruvate carboxykinase (PEPCK; EC 4.1.1.32), pyruvate carboxylase (PC; EC 6.4.1.1.), and glucose-6-phosphatase (G-6-Pase, EC 3.1.3.9)], and one glycolytic enzyme [pyruvate kinase (PK; EC 2.7.1.40)] by established procedures. The activity of PK was not affected by TCDD at either time point. The activity of G-6-Pase tended to be decreased in TCDD-treated animals, as compared to pair-fed controls, but the decrease was variable without an apparent dose-response. The activity of PEPCK was significantly decreased 2 days after dosing, but a clear dose-response was apparent only at the 8-day time point. Maximum loss of activity at the highest dose was 56% below pair-fed control levels. PC activity was slightly decreased 2 days after TCDD treatment and displayed statistically significant, dose-dependent reduction by 8 days after dosing with a 49% loss of enzyme activity after the highest dose. It is concluded that inhibition of gluconeogenesis by TCDD previously demonstrated in vivo is probably due to decreased activities of PEPCK and PC. The data also support the prevailing view that PEPCK and PC are rate-determining enzymes in gluconeogenesis.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 2
    Digitale Medien
    Digitale Medien
    Springer
    Archives of toxicology 64 (1990), S. 66-71 
    ISSN: 1432-0738
    Schlagwort(e): 2,3,7,8-Tetrachlorodibenzo-p-dioxin ; Hypoglycemia ; Gluconeogenesis ; Hypophysectomy ; Corticosterone
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The effect of a usually lethal dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 125 μg/kg) was studied on the conversion of14C-alanine into14C-glucose in male Sprague-Dawley rats by established procedures (determination of plasma alanine and blood glucose by enzymatic assays and isolation of14C-alanine and14C-glucose from whole blood by column chromatography). TCDD-treated rats converted significantly (p 〈 0.05) less14C-alanine into14C-glucose than did their pair-fed or ad libitum-fed counterparts, indicating reduced gluconeogenesis as a result of TCDD treatment. This finding suggests that reduced gluconeogenesis in TCDD-treated rats contributed to the progressively developing, severe hypoglycemia observed in these animals. Corticosterone, a key hormone in gluconeogenesis, provides partial protection from TCDD-induced toxicity in hypophysectomized rats. Therefore, the conversion of14C-alanine into14C-glucose was also determined in hypophysectomized rats dosed with TCDD (125 μg/kg) and given corticosterone (25 μg/ ml in drinking water). These rats also converted significantly (p 〈0.05) less14C-alanine into14C-glucose than did their pair-fed counterparts. However, in contrast to non-hypophysectomized TCDD-treated rats, these rats maintained marginal normoglycemia even at 64 days after dosing with TCDD, which suggests that the partial protective effect of corticosterone in hypophysectomized, TCDD-treated rats is unrelated to its effect on gluconeogenesis. The protection provided by corticosterone supplementation in TCDD toxicity is more likely due to reduced peripheral utilization of glucose enabling the animals to maintain marginal normoglycemia.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 3
    ISSN: 1432-0738
    Schlagwort(e): 2,3,7,8-Tetrachlorodibenzo-p-dioxin ; 1,2,3,7,8-Pentachlorodibenzo-p-dioxin ; 1,2,3,4,7,8-Hexachlorodibenzo-p-dioxin ; 1,2,3,4,6,7,8-Heptachlorodibenzo-p-dioxin ; Mixture ; Structure-activity relationship ; Acute toxicity ; Phosphoenolpyruvate carboxykinase ; Pyruvate carboxylase ; γ-Glutamyl transpeptidase
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Male Sprague-Dawley rats were treated with an LD20, LD50 and LD80 respectively, of tetra-, penta-, hexa-,hepta-CDD and a mixture of the four CDDs, all carrying chlorine substituents in the biologically crucial 2, 3, 7, and 8 positions. Specific activities of two key enzymes of gluconeogenesis, viz, phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate carboxylase (PC), as well as the activity of the preneoplastic marker enzyme γ-glutamyl transpeptidase (γ-GT), were determined in livers of CDD-treated and ad libitum-fed control animals. PEPCK activity showed evidence for dose-related inhibition on the second day after dosing; PC activity was slightly reduced, whereas γ-GT activity was dose-dependently inhibited. By 8 days after dosing PEPCK activities were dose-dependently decreased after administration of all four CDDs and their mixture. PC activities were significantly reduced, but no dose-response was evident. The activity of γ-GT was dosedependently inhibited, but only to a value of 25% below control activities. It is concluded that CDDs share a common mechanism of acute toxicity, viz, inhibition of glucocorticoid-dependent enzymes which results in a derailment of intermediary metabolism not compatible with survival of the animals.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 4
    ISSN: 1432-0738
    Schlagwort(e): 2,3,7,8-Tetrachlorodibenzo-p-dioxin ; 1,2,3,7,8-Pentachlorodibenzo-p-dioxin ; 1,2,3,4,7,8-Hexachlorodibenzo-p-dioxin ; 1,2,3,4,6,7,8-Heptachlorodibenzo-p-dioxin ; Mixture ; Structure-activity relationship ; Acute toxicity ; Plasma tryptophan ; Ethoxyresorufin O-deethylase
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Male Sprague-Dawley rats were treated with an LD20, an LD50, and an LD80 of 2,3,7,8-tetrachlorodibenzop-dioxin (tetra-CDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (penta-CDD), 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (hexa-CDD), 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (hepta-CDD), respectively, and a mixture of the four homologues where each CDD was represented at one-fourth its previously established LD20, LD50, and LD80, respectively. Plasma tryptophan levels, liver ethoxyresorufin O-deethylase (EROD) activities, and liver weights were determined at 2 and 8 days after treatment. Plasma tryptophan levels were dose-dependently elevated, particularly at 8 days after treatment, by as much as 75% over control levels. EROD activity in CDD-treated animals was induced 27- to 28-fold, as compared with vehicle-treated controls, but did not show any dose-response. Liver weights were also significantly increased by the CDD treatments, but the increase was not dose related. There was no correlation between plasma tryptophan levels, a biomarker of acute toxicity of CDDs, and EROD activity, a biomarker of arylhydrocarbon (Ah) receptor-mediated enzyme induction. It is concluded that the acute toxicity of CDDs, which correlates and shows perfect structure-activity relationship with reduced activities of key enzymes of intermediary metabolism, and the induction of enzymes by much lower doses of CDDs in the liver, have different mechanisms of action.
    Materialart: Digitale Medien
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