Comparative toxicity of four chlorinated dibenzo-p-dioxins (CDDs) and their mixture. Part II: Structure-activity relationships with inhibition of hepatic phosphoenolpyruvate carboxykinase, pyruvate carboxylase, and gamma-glutamyl transpeptidase activities.
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 gamma-glutamyl transpeptidase (gamma-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 gamma-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 gamma-GT was dose-dependently 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.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7717.
L W
LW
Weber
M
M
Lebofsky
B U
BU
Stahl
A
A
Kettrup
K
K
Rozman
D000818:Animals; D004147:Dioxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives* / Q000633:toxicity; D011766:Pyruvate Carboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; C051452:1,2,3,7,8-pentachlorodibenzo-p-dioxin; C078219:1,2,3,4,7,8-hexachlorodibenzodioxin; D005723:gamma-Glutamyltransferase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D011766:Pyruvate Carboxylase; C046839:1,2,3,4,6,7,8-heptachlorodibenzodioxin