Activation of 3':5'-cyclic AMP-dependent protein kinase and induction of ornithine decarboxylase as early events in induction of mixed-function oxygenases.
The parenteral administration of a single dose of 3-methylcholanthrene to rats caused an increase in the liver of the concentration of 3', 5'-cAMP and of the activity of cAMP-dependent protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37). These events were followed by an increased activity of ornithine decarboxylase (L-ornithine carboxy-lase, EC 4.1.1.17), the enzyme that controls the biosynthesis of polyamines. Finally, the activity of benzo[a]pyrene hydroxylase, as well as the amount of cytochrome P-448, was increased. Similarly, after the administration of phenobarbital, there was first an increase in the cAMP concentration and in the activity of cAMP-dependent protein kinase, then the induction of ornithine decarboxylase, and finally, an enhanced activity of ethylmorphine N-demethylase and an increased content of cytochrome P-450. These data suggest that the drug-induced processes in liver that increase the activities of the oxidative, and presumably other, drug-metabolizing enzymes include the following sequence of events: (1) increase in cAMP concentration and/or activation of cAMP-dependent protein kinase; (2) induction of ornithine decarboxylase; and, (3) induction of drug-metabolizing enzymes.
D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000096:biosynthesis; D002262:Carboxy-Lyases / Q000096:biosynthesis*; D000242:Cyclic AMP / Q000378:metabolism* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction; D005037:Ethylmorphine-N-Demethylase / Q000096:biosynthesis; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D010088:Oxidoreductases / Q000096:biosynthesis*; D010634:Phenobarbital / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats
D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D000242:Cyclic AMP; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D001579:Benzopyrene Hydroxylase; D005037:Ethylmorphine-N-Demethylase; D011494:Protein Kinases; D010727:Phosphoric Diester Hydrolases; D002262:Carboxy-Lyases; D009955:Ornithine Decarboxylase; D010634:Phenobarbital