Possible involvement of cyclic amp-dependent protein kinase in p, p′-ddt-induced changes in hepatic metabolism

Abstract

Administration of an acute dose of p, p-1,1,1-trichloro-2,2-bis ( p-chlorophenyl) ethane ( p, p′-DDT) (600 mg/kg, p.o.) resulted in a significant increase in hepatic adenylate cyclase activity (40 per cent) and endogenous cyclic AMP levels (31 per cent). Although the cytosol cyclic AMP-independent protein kinase activity was only slightly affected (18 per cent), the activity of the nucleotide-dependent enzyme was significantly decreased to 74 per cent of the control values. Whereas the protein kinase activity ratio (−cyclic AMP/+cyclic AMP) of this soluble enzyme was increased, the ability of the enzyme to bind [ 3H]cyclic AMP in vitro was significantly decreased after pesticide administration. As observed with the soluble enzyme, maximal stimulation of the crude nuclear protein kinase (1500 g pellet) was observed 1 hr after p, p′-DDT treatment, as indicated by changes in the phosphorylation of endogenous nuclear substrates and cyclic AMP-binding capacity. Studies with lower dosages of DDT revealed that a dose as low as 100 mg/kg was sufficient to produce statistically significant alterations in the activities of both the soluble and paniculate enzymes. In most cases, doubling the dosage (200 mg/kg) resulted in greater changes in these biochemical parameters. The present study supports the concept that the DDT-induced alterations in hepatic carbohydrate metabolism may be related to an initial stimulation of the hepatic cyclic AMP-adenylate cyclase-protein kinase system.