Relationships between Hepatic Enzyme Induction, Glutamate Formation, and Purine Nucleotide Biosynthesis in Glucocorticoid Action

Abstract

Abstract 1. Among the earliest and most sensitive consequences of glucocorticoid action are acceleration in the rate of purine nucleotide biosynthesis in liver and inhibition of this metabolic pathway in the thymus and spleen. 2. Hepatic tyrosine-α-ketoglutarate transaminase induction occurs concurrently with the accelerated hepatic purine nucleotide biosynthesis; these metabolic alterations in the liver precede inhibited thymic purine nucleotide and protein metabolism. 3. The product of tyrosine transaminase catalysis, glutamic acid, administered parenterally to adrenalectomized rats, mimics cortisone in stimulating in liver and inhibiting in thymus the rates of purine nucleotide and protein biosyntheses. These facts are compatible with the hypothesis that augmented gluconeogenesis and hepatic transaminase induction following glucocorticoid administration result in enhanced glutamate formation, which influences hepatic and thymic purine nucleotide and protein biosynthesis. Thus, hepatically generated glutamate may serve as an amplifying mechanism by which glucocorticoids influence metabolic processes in various target organs. 4. Analytically demonstrable liver glycogen deposition occurs only after impairment of thymic metabolism and following elevation of the blood sugar levels. Thus, glycogen deposition is a relatively secondary and late consequence of glucocorticoid action. 5. Orotate-5-3H incorporation into liver acid-soluble uridine monophosphate is only slightly influenced by cortisone, whereas its incorporation into ribonucleic acid is significantly elevated, thus providing isotopic evidence for hormonally enhanced generalized hepatic ribonucleic acid biosynthesis.