Abstract
Abstract The N6,O2'-dibutyryl analogue of cyclic adenosine 3',5'-monophosphate (dibutyryl cyclic AMP) elevates the level of hepatic tyrosine-α-ketoglutarate transaminase (l-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5) some 3- to 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 carboxy-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 3- to 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.
Highlights
Glucagon elevates the intracellular level of cyclic AMP2 in liver [4], and recently we have found that cyclic AMP, as well as glucagon, is capable of inducing tyrosine transaminase in fetal rat liver maintained in organ culture [5,6,7]
The first indication that cyclic AMP might induce tyrosine transaminase in Go came from experiments in which theophylline (2 mg at 0 and 3 hours) was injected along with repeated doses of glucagon (50 pg per hour)
The results presented in this paper support the conclusion that cyclic AMP is the intrahepatic mediator of the action of glucagon on enzyme synthesis in tivo
Summary
Materials-Male rats from the Charles River Breeding Laboratories were used throughout these experiments. Glucagon and insulin were obtained from Sigma. Dibutyryl cyclic AMP was obtained from Calbiochem and from Schwarz BioResearch. Both preparations had essentially the same effectiveness on a weight basis. The protein-free diet was obtained from General 13iochemicals. The antiserum to tyrosine transaminase and the partially purified transaminase used as carrier in the immunochemical experiments were prepared as described previously [8]
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