Induction of hepatic enzyme synthesis in vivo by adenosine 3', 5'-monophosphate.

The N6,02’-dibutyryl analogue of cyclic adenosine 3’,5’monophosphate (dibutyryl cyclic AMP) elevates the level of hepatic tyrosine-cr-ketoglutarate transaminase (L-tyrosine: 2-oxoglutarate aminotransferase, EC 2.6.1.5) some 3to 6-fold in intact and adrenalectomized rats. The response of this enzyme is more rapid to dibutyryl cyclic AMP than to any other inducer of the transaminase. Hourly injection of dibutyryl cyclic AMP can maintain the elevated transaminase level for at least 5 hours. The rate of synthesis of tyrosine transaminase, as measured by an isotopic-immunochemical procedure, is enhanced by treatment with dibutyryl cyclic AMP. There is no detectable effect of dibutyryl cyclic AMP on the synthesis of total soluble proteins, however. Combinations of dibutyryl cyclic AMP and hydrocortisone produce additive or, in some cases, synergistic increases in transaminase activity, but the responses to combinations of dibutyryl cyclic AMP and either glucagon or insulin are not additive. Two other soluble liver enzymes, P-enolpyruvate carboxykinase (GTP:oxaloacetate car-boxy-lyase transphosphorylating, EC 4.1.1.32) and serine dehydrase (L-serine hydro-lyase, EC 4.2.1.13) are also elevated by treatment of intact rats with either dibutyryl cyclic AMP or glucagon, but another, tryptophan pyrrolase (L-tryptophan : oxygen oxidoreductase, EC 1.13.1.12, tryptophan oxygenase), is not affected by either agent. Hydrocortisone induces both the transaminase and pyrrolase 3to 5-fold but the steroid has no effect on either the carboxykinase or the dehydrase. The results support the view that cyclic AMP is the intracellular mediator of the action of glucagon on hepatic enzyme synthesis.