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Key enzymes of gluconeogenesis are dose-dependently reduced in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats

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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.

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Abbreviations

ADP:

adenosine diphosphate

ATP:

adenosine triphosphate

EDTA:

ethylenediamine tetraacetic acid

G-6-Pase:

glucose-6-phosphatase

LDH:

lactate dehydrogenase

NADH:

reduced nicotinamide adenine dinucleotide

PEPCK:

phosphoenolpyruvate carboxykinase

PC:

pyruvate carboxylase

PK:

pyruvate kinase

TCDD:

2,3,7,8-tetrachlorodibenzo-p-dioxin

Tris:

trishydroxymethyl aminomethane

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Authors and Affiliations

  1. Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 39th and Rainbow Blvd, 66103, Kansas City, Kansas, USA

    Lutz W. D. Weber, Margitta Lebofsky &  Karl Rozman

  2. Institut für Toxikologie, Gesellschaft für Strahlen- und Umweltforschung mbH München, W-8042, Neuherberg, FRG

    Lutz W. D. Weber, Helmut Greim &  Karl Rozman

Authors
  1. Lutz W. D. Weber
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  2. Margitta Lebofsky
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  3. Helmut Greim
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  4. Karl Rozman
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Dedicated to Professor Dr. Gerhard Zbinden on the occasion of his retirement

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Weber, L.W.D., Lebofsky, M., Greim, H. et al. Key enzymes of gluconeogenesis are dose-dependently reduced in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats. Arch Toxicol 65, 119–123 (1991). https://doi.org/10.1007/BF02034937

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  • DOI: https://doi.org/10.1007/BF02034937

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