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Search for antiglucocorticoid activity in rat liver in vivo
Abstract:
Estradiol and testosterone both lowered endogenous liver glycogen and at 20-fold higher doses impaired triamcinolone acetonide mediated glyconeogenesis in adult adrenalectomized male rats. Neither steroid influenced liver tyrosine transaminase although tryptophan pyrrolase activity was depressed by testosterone. Progesterone increased liver tryptophan pyrrolase but did not influence other parameters. Cortexolone did not alter either of these processes whereas cortisol induced both enzymes and, at much higher dose levels, gluconeogenesis. Binding of 3H-triamcinolone acetonide to its cytoplasmic receptor in vitro was left unaffected in presence of 20-fold greater concentration of either sex steroid but almost totally abolished by cold, homologous molecules. Similar results were obtained by 3H-cortisol except that estradiol partially competed for 3H-cortisol binding sites even at 20-fold greater concentrations of cold estradiol. Separation on DEAE-cellulose-52 and Ultrogel 44 columns revealed binding of all steroids to macromolecules of comparable physicochemical properties although the ratios of binding to the various subpopulations of the receptor were a function of the steroid in question. These results are discussed in terms of sex steroid binding to different moieties of a complex, heterogeneous, polymorphic protein rather than inhibition of binding to the active configuration acquired in presence of an inducer.
Insights
Sex hormones like estradiol and testosterone affect liver glycogen and gluconeogenesis in rats. These steroids interact with receptor proteins, suggesting complex binding dynamics rather than simple inhibition.
Area of Science:
- Endocrinology
- Hormone Action
- Biochemistry
Background:
- Sex steroids (estradiol, testosterone, progesterone) and glucocorticoids (cortisol, triamcinolone acetonide) play crucial roles in metabolic regulation.
- Understanding the interplay between these hormone classes at the molecular level is essential for comprehending physiological and pathophysiological processes.
Purpose of the Study:
- To investigate the effects of various steroids on hepatic gluconeogenesis and related enzyme activities in adrenalectomized male rats.
- To examine the in vitro binding interactions of sex steroids and glucocorticoids with their respective cytoplasmic receptors.
Main Methods:
- Administration of estradiol, testosterone, progesterone, cortexolone, and cortisol to adrenalectomized male rats.
- Measurement of endogenous liver glycogen, gluconeogenesis, liver tyrosine transaminase, and tryptophan pyrrolase activity.
- In vitro receptor binding assays using radiolabeled triamcinolone acetonide and cortisol in the presence of varying steroid concentrations.
- Chromatographic separation (DEAE-cellulose-52 and Ultrogel 44) of steroid-macromolecule complexes.
Main Results:
- Estradiol and testosterone reduced liver glycogen and impaired triamcinolone acetonide-induced gluconeogenesis at high doses.
- Testosterone decreased tryptophan pyrrolase activity, while progesterone increased it; neither affected tyrosine transaminase.
- Cortisol induced both enzymes and gluconeogenesis.
- Sex steroids did not inhibit triamcinolone acetonide or cortisol binding to their receptors, but estradiol partially competed for cortisol binding sites.
- Steroids bound to macromolecules with similar properties, but binding ratios varied, suggesting differential interactions with receptor subpopulations.
Conclusions:
- Sex steroids modulate hepatic glucose metabolism and enzyme activities independently of direct glucocorticoid receptor antagonism.
- The observed binding patterns suggest that sex steroids interact with distinct components of a heterogeneous receptor system, rather than inhibiting the formation of an active hormone-receptor complex.