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Rozman, K.K. ; Lebofsky, M. ; Stahl, B.U. ; Weber, L.W.D.

The Role of Insulin and Corticosterone in the Toxicity of Dioxins.

Chemosphere 25, 79-82 (1992)

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Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.

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TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) alters the homeostasis of numerous hormones among them that of corticosterone and insulin. Hormonal status in turn affects toxicity of TCDD as shown by rapid exitus in response to nontoxic doses of insulin and a shifting of the dose response curve to the left in adrenalectomized rats. These two hormones are key regulators of PEPCK (phosphoenolpyruvate carboxykinase), which is the rate determining enzyme of gluconeogenesis. PEPCK end hence gluconeogenesis is dose-dependently inhibited by TCDD and its penta-, hexa- and hepta-chloro homologues as well as their mixture revealing an essentially perfect structure/activity relationship and strict additivity in their inhibitory effect. This structure/activity relationship shows a highly significant correlation with the structure/activity relationship of acute toxicity suggesting that inhibition of PEPCK is the key lesion in the toxicity of dioxins and of all other compounds acting by this mechanism. Inhibition of PEPCK is a very early effect beginning 4 to 8 hrs after an oral dose of TCDD and it is at maximum by 16 hrs after dosing. Amount of PEPCK-protein (Western blot) and PEPCK-mRNA (Northern blot) reflect the decreased activity of PEPCK suggesting that TCDD reduces the transcription of the PEPCK gene. Hormonal changes (insulin and corticosterone) are not apparent until 4 to 8 days after dosing indicating that they are secondary to an earlier lesion and as such they represent a response of the organism to the primary insult. Moreover, hormonal changes (decreased insulin and increased corticosterone) are consistent with maximum stimulation of PEPCK (as in the case in pair-fed controls) and yet PEPCK is dose-dependently inhibited. Therefore, we suggest that the mechanism of action of dioxins consists of an interaction with the PEPCK gene which renders the insulin- and glucocorticoid-responsive regions nonresponsive to endogenous stimuli.

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