title: 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.
abstract: 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 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-induced lethality in rats. This study was carried out to further analyse the toxicological significance of reduced gluconeogenesis by comparing dose-responses and time-courses of effects of TCDD on the activity of phosphoenolpyruvate carboxykinase (PEPCK) in liver, liver glycogen concentration as well as plasma concentrations 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-dependent 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 liver 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, since a similar decrease was seen in pair-fed controls. Decreases in plasma glucose concentrations were also more profound in L-E rats than in H/W rats, but pair-fed controls were generally less affected. Circulating concentrations of amino acids were markedly increased in TCDD-treated L-E rats, which is likely to reflect increased mobilization of amino acids and their decreased metabolism in liver. Reduction of liver PEPCK activity cannot account for the sensitivity difference of these two strains of rats in terms of mortality. Nevertheless, the response of both strains of TCDD-treated rats regarding gluconeogenesis is different from that seen in pair-fed controls and suggesting that impairment of this pathway contributes to the development of the wasting syndrome.
authors.affiliation: National Public Health Institute, Laboratory of Toxicology, P.O. Box 95, FIN-70701 Kuopio, Finland. matti.viluksela@ktl.fi
authors.forename: M
authors.initials: M
authors.lastname: Viluksela
authors.forename: M
authors.initials: M
authors.lastname: Unkila
authors.forename: R
authors.initials: R
authors.lastname: Pohjanvirta
authors.forename: J T
authors.initials: JT
authors.lastname: Tuomisto
authors.forename: B U
authors.initials: BU
authors.lastname: Stahl
authors.forename: K K
authors.initials: KK
authors.lastname: Rozman
authors.forename: J
authors.initials: J
authors.lastname: Tuomisto
mesh_terms: D000596:Amino Acids / Q000097:blood*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004351:Drug Resistance; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005943:Gluconeogenesis / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D014508:Urea / Q000097:blood
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D004785:Environmental Pollutants; D008112:Liver Glycogen; D000072317:Polychlorinated Dibenzodioxins; D014508:Urea; D019363:Cytochrome P-450 CYP1A1; D010729:Phosphoenolpyruvate Carboxykinase (GTP)