Decreased hepatic phosphoenolpyruvate carboxykinase gene expression after 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment: implications for the acute toxicity of chlorinated dibenzo-p-dioxins in the rat.
Decreased activity of the rate limiting gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), has been recently suggested to be the critical lesion in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We now show that other toxicologically relevant chlorinated dibenzo-p-dioxins (CDDs), with chlorine substituents in the crucial 2-,3-,7-, and 8-positions, exert the same effect on PEPCK activity. The doses required to cause this enzyme inhibition are within the acutely toxic range for each homologue, suggesting the same mechanism of action for these compounds. To further investigate the mechanism whereby dioxins decrease PEPCK activity, Northern analysis was performed using a cDNA probe complementary to a portion of the PEPCK mRNA. We could demonstrate that after TCDD treatment hepatic PEPCK mRNA was decreased by as much as 90% compared to pair-fed control animals (day 8 after dosing). This decrease in PEPCK mRNA was paralleled by a decrease of the amount of PEPCK protein and enzymatic activity. These results indicate that the physiological changes which occur in TCDD-treated animals (decreased feed consumption, low plasma insulin and elevated plasma corticosterone levels) which under normal conditions increase PEPCK gene expression and enzyme activity, are not effective in stimulating PEPCK synthesis in TCDD-treated animals.
Stahl
B U
BU
Dept. of Pharmacol., Tox. and Therap., University of Kansas Med. Ctr., Kansas City 66103.
Beer
D G
DG
Weber
L W
LW
Lebofsky
M
M
Rozman
K
K
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D004147:Dioxins / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics* / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D010729:Phosphoenolpyruvate Carboxykinase (GTP)