Molecular Pharmacology, Vol 8, 345-352, Copyright © 1972 by the American Society for Pharmacology and Experimental Therapeutics

Increase of Hepatic L-Phenylalanine: Pyruvate Aminotransferase by Glucagon in Rats

Possible Role of Adenosine Cyclic 3',5'-Monophosphate as a Mediator

¹ Division of Biochemical and Physiological Research, The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46206

Glucagon caused an approximately 4-fold increase in hepatic L-phenylalanine: pyruvate aminotransferase activity in rats 24 hr after subcutaneous injection: Tetraiodo, mononitro, and monodeamido derivatives of glucagon also increased enzyme activity, the tetraiodoglucagon being more active than glucagon itself. Theophylline, an inhibitor of cyclic AMP phosphodiesterase, enhanced the action of glucagon in increasing phenylalanine aminotransferase. Higher doses of theophylline and of epinephrine, which, like glucagon, can stimulate adenyl cyclase, also increased the activity of this enzyme in both intact and adrenalectomized rats. N⁶, O²-Dibutyryl cyclic AMP likewise increased the enzyme, and theophylline greatly potentiated its action. The results are consistent with a role for cyclic AMP as a mediator in the elevation of hepatic phenylalanine aminotransferase. This enzyme was shown to be distinct from alanine aminotransferase, in that the former enzyme could be elevated by glucagon or dibutyryl cyclic AMP or particularly inactivated by freezing, independently of alanine aminotransferase, whereas alanine aminotransferase could be elevated by deprivation of food or inhibited by p-chloromercuribenzoate independently of phenylalanine aminotransferase. Liver extracts catalyzed the transamination of phenylalanine with either pyruvate or 2-oxoglutarate as the amino acceptor, but only the phenylanine:pyruvate transamination was increased by prior 24-hr treatment with glucagon. Phenylalanine aminotransferase activity in heart and kidney was as high as in the liver; brain had lower activity. Glucagon did not affect the enzyme in tissues other than the liver.