Metabolic effects of glucocorticoids as related to enzyme induction

Abstract The concept that glucocorticoid induction of the hepatic amino acid metabolizing enzymes, tyrosine-α-ketoglutarate transaminase and tryptophan pyrrolase, assumes an important role in the processes by which this hormone manifests many of its regulatory functions has been investigated from several points of view. In a search for the mechanisms by which glucocorticosteroids effect induction of these enzymes, inquiry into the effects of cortisone on the biosynthetic pathway leading to RNA was undertaken. It was found that incorporation in vivo of isotopically labeled precursors into liver RNA was rapidly and markedly enhanced after administration of a single low dose of cortisone, with a time course parallel to that of glucocorticoid induction of increased enzyme protein and activity. However, the following evidence has been accumulated which suggests that little, if any, of the observed stimulation in isotopic incorporation into RNA after cortisone administration is attributable to enhanced elaboration of RNA molecules from their nucleotide precursors: (1) the magnitude of cortisone induced stimulation of incorporation of various labeled precursors into liver RNA varies markedly, glycine- 14 C > inorganic 32 P > rotate- 3 H; (2) cortisone administration rapidly elevates incorporation in vivo of glycine- 14 C into liver acid soluble adenine nucleotides to a greater extent and with similar kinetics as incorporation of this precursor into RNA; (3) the stimulation of isotope incorporation into RNA of all liver subcellular compartments are of similar orders of magnitude and time course; (4) accumulation of increased quantities of hepatic RNA is observed only many hours after large doses of cortisone, at a time when enzyme induction has already subsided; (5) in vitro studies provide no evidence of glucocorticosteroid intervention in the synthesis of RNA on the DNA template, since neither binding of glucocorticoids with purified rat liver DNA nor alteration of the secondary structure of native DNA by these steroids could be detected. The only isotopic evidence suggesting possible enhancement of RNA elaboration following glucocorticoid administration is the observation of a slight stimulation in incorporation of orotate- 3 H into hepatic RNA which exceeds a yet smaller stimulation in incorporation of this isotope into a pyrimidine nucleotide precursor pool. That stimulation of hepatic purine biosynthesis does occur as a marked and early response to glucocorticoids has been established. Investigation of the mechanism of hormonal regulation of purine metabolism has revealed that intraperitoneal administration to adrenalectomized rats of l -glutamate, l -alanine, l -leucine, their d -counterparts, inorganic ammonium salts and l -glutamine, all mimic cortisone in the stimulation of glycine- 14 C incorporation into acid-soluble adenine. It has been accordingly proposed that glucocorticoid induction of transaminase activity may result in sequential expansion in the routes of amino nitrogen transport, leading to the observed enhancement in purine nucleotide biosynthesis—“purinoneogenesis”—as well as gluconeogenesis and increased urea output, all of which are characteristic of the cortisonized animal. Changes in liver amino acid patterns following cortisone administration are consistent with this working hypothesis: liver tyrosine levels are depressed; concentrations of glutamate and aspartate, amino acids pivotal in transamination, are elevated. Extension of these studies to extra hepatic target tissues, has revealed that simultaneous with stimulated glycine-2- 14 C incorporation into protein and acid-soluble purine in the liver, cortisone evokes a marked depression in these metabolic pathways in the lymphoid tissues, thymus and spleen.