Inhibition of phosphoenolpyruvate carboxykinase activity appears to be the key biochemical lesion in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exerts its acute toxicity by inducing a gradually increasing voluntary feed refusal. However, this seems not to be caused by a direct effect on the central nervous system, as far higher concentrations of TCDD were found in the brain after intracerebroventricular (i.c.v.) than after lethal intravenous (i.v.) injections, but were not accompanied by a wasting syndrome. TCDD causes inhibition of several key enzymes of gluconeogenesis, with phosphoenolpyruvate carboxykinase (PEPCK) responding earliest and strongest to the insult. Responses of pyruvate carboxylase (PC) and glucose-6-phosphatase (G-6-Pase) are less pronounced and begin at later time points. Blood and brain levels of tryptophan increase following TCDD treatment with a lag period of about three days, shortly after the decrease of PEPCK activity becomes apparent. Since thi samino acid is the precursor of the appetite suppressant neurotransmitter serotonin, and since it is normally degraded via gluconeogenesis, a series of events can be suggested to explain the TCDD-induced wasting syndrome. By an as yet unrevealed mechanism TCDD decreases the activity of PEPCK to about 40 percent of normal, leading to a back-up of gluconeogenic substrates, among them tryptophan, which in turn can further inhibit PEPCK activity in vivo. This causes an increase in serotonin turnover in brain and possibly in other tissues. Increased serotonergic activity in turn is likely to play an important role in the increasing feed refusal of TCDD-treated rats which eventually leads to death