Molecular Pharmacology, Vol 12, 871-878, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Adenosine Cyclic 3',5'-Monophosphate-Dependent Protein Kinase and Ornithine Decarboxylase Involvement in the Induction of Cytochrome P-450 and Hepatic Hypertrophy

¹ Department of Pharmacology, University of Arizona Medical Center, Tucson, Arizona 85724

The administration of a single dose of Aroclor-1254 (500 mg/kg intraperitoneally) resulted in a biphasic response in rat liver of the activation of cyclic 3',5'-AMP-dependent protein kinase, the induction of ornithine decarboxylase, and the activation of RNA polymerase I. The first cycle of this biphasic response involved activation of cyclic AMP-dependent protein kinase from 2 to 6 hr (177% of control), increased activity of ornithine decarboxylase from 3.5 to 6 hr, and elevation of RNA polymerase I activity from 4 to 6 hr after drug administration. By 8 hr activities of these enzymes had essentially returned to control levels. However, between 10 and 20 hr, cyclic AMP dependent protein kinase activity again rose to about 170% of control, followed by elevated activities of ornithine decarboxylase and RNA polymerase I. The maximal stimulation of ornithine decarboxylase activity was 5-6-fold in both phases of its response, and RNA polymerase I activity was maximal (150% of control) at 5 and 20 hr. Hepatic cytochrome P-450 concentration was increased within 6 hr after a single dose of Aroclor-1254 and reached a maximal concentration of 4 times the control level by 8 days. The liver weight to body weight ratios in rats given the drug were about 150% of control within 2 days and maintained this level through 15 days. Aminophylline and/or dibutyryl cyclic AMP given together with a single low dose of Aroclor-1254 (50 mg/kg) resulted in a greater increase in cytochrome P-450 concentration than did a low dose of Aroclor-1254 administered alone. These data support the concept that the activation of cyclic AMP-dependent protein kinase, elevation of ornithine decarboxylase activity, and enhanced RNA polymerase I activity form a tight temporal sequence of biochemical events that are related to drug-induced liver hypertrophy and to microsomal enzyme induction.

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