Adaptive response of hepatic carbohydrate metabolism to oral administration of p, p′-1,1,1 -trichloro-2,2- bis ( p-chlorophenyl)ethane in rats

Abstract

The effects of an acute dose of p, p′-1,l,1-trichloro-2,2- bis ( p-chlorophenyl)ethane ( p, p′-DDT) have been investigated on the activities of pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-diphosphatase and glucose 6-phosphatase in rat liver. Administration of p, p′-DDT (600 mg/kg, p.o.) produced 2- to 2.5-fold stimulation of these key gluconeogenic enzymes in 5 hr, although statistically significant increases could be detected at 1 hr. Blood glucose increased as early as 0.5 hr, attained peak values at 1 hr, and then declined to reach control levels m 3–5 hr. In contrast, hepatic glycogen decreased gradually to 47 per cent of the control values in 1 hr, and was restored by 3 hr following treatment with this insecticide. Administration of p, p′-DDT to adrenalectomized rats produced similar changes in blood glucose and hepatic glycogen, suggesting that the insecticide-induced hyperglycemia and glycogenolysis may not be mediated by a release of catecholamines from the adrenals. Doseresponse studies revealed that 100 mg/kg of p, p′-DDT was the minimal amount necessary to induce statistically significant increases in the activities of hepatic pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-diphosphatase and glucose 6-phosphatase. Maximal stimulation of the four key gluconeogenic enzymes was seen generally at 5 hr when rats were treated with a 400–600 mg/kg dose of p, p′-DDT. Daily administration of small doses of p, p′-DDT (5 or 25 mg/kg) for 45 days also resulted in significant enhancement in the activities of various hepatic gluconeogenic enzymes. Actinomycin D, cycloheximide or ethionine failed to affect the basal levels of either of these hepatic enzymes, but effectively reduced the insecticide-induced increases in various enzyme activities. Treatment of adrenalectomized rats with p, p′-DDT enhanced various hepatic enzymes to a degree similar to that observed in intact animals. Furthermore, administration of triamcinolone to p, p′-DDT-treated adrenalectomized rats did not potentiate the action of the insecticide on any of the gluconeogenic enzymes examined. Our results suggest that treatment with p, p′-DDT produces marked increases in the quartet of key, rate-limiting gluconeogenic enzymes in hepatic tissue which are not mediated through a release of corticosteroids from adrenal glands.