H. Traikov

Distribution, metabolism and biological activity of deoxycorticosterone in the central nervous system

Intravenously injected [1,2-3H]deoxycorticosterone (DOC) readily enters all parts of the central nervous system. In intact and eviscerated rats the highest concentration of radioactive label was recovered from areas corresponding to the reticular formation from the brain stem. In addrenalectomized animals, in addition to high brain stem concentration, there was also a marked increase in the uptake of radioactivity in the septum, hippocampus and pituitary. Data from the eviscerated rat point to a uniform distribution of [1,2-3H]DOC in neural tissues and suggest that the higher levels of radioactivity found in the brain stem may be due to a DOC metabolite with the chromatographic characteristics of allo-tetrahydro-DOC, an anaesthetic-type steroid. A decrease in the amplitude of evoked sciatic potentials in brain stem sites but not in the thalamic relay nucleus was observed in 52% of the cases studied, following the i.v. injection of 100-150 mug DOC.

The effects of corticosterone, 18-OH-DOC, DOC and 11β-hydroxyprogesterone on the adrenal pituitary axis of the stressed rat

Abstract The in vivo effects of steroids native to the rat on the adrenocortical response to ether stress or to stress induced by a change of environment were studied in young male Sprague-Dawley rats. Corticosterone, 11β-hydroxyprogesterone and deoxycorticosterone at a dose of 1 mg per 100 g daily for 3 days, were effective to a similar degree in suppressing adrenal-pituitary function in the stressed rat as evidenced by a marked decrease in circulating corticosterone levels. Diminished adrenocortical activity in the steroid-treated animals was further indicated by a greatly reduced in vitro production of ultra-violet absorbing, Porter-Silber positive and fluorescent steroids and by a low corticosterone content in the gland. Under similar conditions 18-hydroxydeoxycorticosterone was either ineffective or slightly stimulated the adrenocortical stress response. Progesterone had no effect. The in vitro response of adrenal glands to ACTH was not impaired following steroid treatment, suggesting that the reduction in adrenocortical function observed not only with corticosterone but also with 11β-hydroxyprogesterone and deoxycorticosterone reflects a decrease in stress-induced ACTH secretion.

Biological consequences of 18-hydroxylation

Abstract Insertion of a hydroxyl group at C-18 modifies the biological properties of some pregnane derivatives as follows: Inserted into deoxycorticosterone (DOC) it (1) reduces or does not affect its sodium-retaining action in rats, (2) impairs or abolishes its potassium-excretory effect, (3) enhances its ability to cause the retention of urine, (4) does not appear to modify the magnitude of the hypertensive response of DOC but could alter the manner by which this response is exerted, (5) invests DOC with anti-inflammatory activity that is more pronounced in the presence than in the absence of the adrenal gland, and (6) invests it with thymolytic potency. 18-Hydroxylation, furthermore, (7) abolishes the inhibitory effect of DOC, and greatly impairs that of corticosterone (B), upon pituitary-adrenal function, (8) appears to confer upon DOC but not upon B, the capacity to inhibit the peripheral metabolism of B, and (9) obliterates the glycolytic effects of DOC, progesterone and B in the adrenal gland. Oxygenation at C-18 to an aldehyde blocks the glycolytic action of B as well, imparts upon B renowned effects on electrolyte metabolism and, also, a greatly increased ability to attenuate pituitary-adrenal function. The chemical consequences of 18-hydroxylation which include the potential for dimerization and cyclization may confer specificity upon the steroid molecule by masking functional groups attractive to some receptors, or by introducing functional groups attractive to others.

Steroid secretion by rat adrenal glands during the first week following adrenal enucleation

Abstract Adrenal venous blood was collected from rats 4 days after adrenal enucleation and from sham operated controls. The amount of regenerated cortical tissue was measured in serial sections of the glands. The newly regenerated adrenal cortex produced per unit adrenal tissue only about 14% of the amount of corticosterone and less than 12% of the amount of 18-OH-DOC secreted by the intact tissue, whereas the production of DOC was not decreased. The relative increase in the amount of DOC available to the rats bearing regenerating adrenal glands might contribute to the sodium retention observed in these rats during the first week after adrenal regeneration.

Adrenal steroid biosynthesis by different species of mouselike rodents

Abstract Adrenals from voles ( Microtus agrestis ), deer mice ( Peromyscus californicus and Peromyscus erimicus ) and albino mice ( Mus musculus ) incubated in Krebs-Ringer bicarbonate medium formed corticosterone as major endogenous end product in vitro and no cortisol was detected. These rodents belong to the superfamily Muroidea. Adrenals from pocket mice ( Perognathus baileyi and Perognathus penicillatus pricei ), of the superfamily Geomyoidea, formed cortisol as a major end product from endogenous sources and no corticosterone or only traces, and the total output of ultraviolet-absorbing steroids by these glands in the presence of ACTH was much lower than that obtained with the adrenals of the Muroidea. The adrenals from Perognathus baileyi also formed cortisol as a major end product from radioactive substrates, but not corticosterone, while the predominant conversion product obtained with vole and albino mouse adrenals was corticosterone, and cortisol was either not found or present in minimal amounts. Cortisol was, further, not recovered when adrenals from 2- to 3-week-old male albino mice were incubated in plasma. Evidence for the endogenous formation of aldosterone and 18-hydroxycorticosterone was obtained in all the species, and the identity of these compounds was established when they were present as radioactive conversion products. The adrenals of Perognathus baileyi converted radioactive progesterone to aldosterone in amounts equaling the conversion to cortisol.

A simple synthesis of 18-hydroxydeoxycorticosterone

Abstract A relatively simple synthesis of 18-hydroxydeoxycorticosterone via 18-hydroxyprogesterone is described.

BIOLOGICAL CONSEQUENCES OF 18-HYDROXYLATION

Insertion of a hydroxyl group at C-18 modifies the biological properties of some pregnane derivatives as follows: Inserted into deoxycorticosterone (DOC) it (1) reduces or does not affect its sodium-retaining action in rats, (2) impairs or abolishes its potassium-excretory effect, (3) enhances its ability to cause the retention of urine, (4) does not appear to modify the magnitude of the hypertensive response of DOC but could alter the manner by which this response is exerted, (5) invests DOC with anti-inflammatory activity that is more pronounced in the presence than in the absence of the adrenal gland, and (6) invests it with thymolytic potency. 18-Hydroxylation, furthermore, (7) abolishes the inhibitory effect of DOC, and greatly impairs that of corticosterone (B), upon pituitary-adrenal function, (8) appears to confer upon DOC but not upon B, the capacity to inhibit the peripheral metabolism of B, and (9) obliterates the glycolytic effects of DOC, progesterone and B in the adrenal gland. Oxygenation at C-18 to an aldehyde blocks the glycolytic action of B as well, imparts upon B renowned effects on electrolyte metabolism and, also, a greatly increased ability to attenuate pituitary-adrenal function. The chemical consequences of 18-hydroxylation which include the potential for dimerization and cyclization may confer specificity upon the steroid molecule by masking functional groups attractive to some receptors, or by introducing functional groups attractive to others.