Tetsuo Uete

Mode of action of glucocorticoids: II. Early effects of triamcinolone on amino acid incorporation into various tissues in vivo

Abstract 1. 1. Acute effects of the glucocorticoid triamcinolone (350 μg per 100 g body weight, 2 to 4 h) on labeled amino acid incorporation into protein of subcellar components in various tissues have been investigated in fed rats. 2. 2. The incorporation of uniformely labeled L -[ 14 C]valine and DL -[3- 14 C]phenylalanine into proteins of nuclei, mitochondria, microsomes and supernatant fractions of hepatic cells was not modified by the administration of triamcinolone, whereas the incorporation of these amino acids into proteins of each of these fractions of the thymus was reduced by triamcinolone given either 2 or 4 h previously. 3. 3. The administration of triamcinolone increased liver glycogen, but did not significantly affect the concentration of blood sugar and muscle glycogen in fed animals. The incorporation of 14 C from uniformely labeled L -[ 14 C]valine as well as DL -[3 14 ]phenylalanine into liver glycogen and blood glucose were s by triamcinolone administration, indicating increased gluconeogenesis from the carbon of phenylalanine as well as from that of valine. 4. 4. The size of the pool of free amino acids and the specific activities of free amino nitrogen in the blood and thymus, were not significantly modified by triamcinolone, but the size of the pool and the radioactivities of free amino acids in hepatic cells were increased. 5. 5. These findings suggest that triamcinolone inhibits protein synthesis in the thymus even in very short-term experiments and that this inhibiting effect is due neither to the effect of hormone on cell membrane transport of amino acids nor to the catabolism of amino acids in the liver for gluconeogenesis with resultant shortage of amino acids for protein synthesis in peripheral tissue.

Autoregulatory system of insulin degradation in liver II. Relationship between blood insulin levels and GSH-dependent insulin degrading activity in liver and blood

An autoregulatory system of insulin degradation in the liver in which the rate of insulin metabolism changes in response to fluctuation in its blood levels, was investigated. In the plasma of rats and man in the absence of reduced glutathione (GSH), insulin degradation was not observed, but when a sufficient amount of reduced glutathione was added, the plasma did degrade insulin. This GSH-dependent insulin degrading activity in plasma was quite similar to that in liver in its nature. In rats, this GSH-dependent insulin degrading activity in the liver and plasma was fluctuated in response to fluctuation in the blood insulin levels, and the GSH-dependent insulin degrading activity in plasma was well correlated with that in the liver. Similarly, in man the GSH-dependent insulin degrading activity in plasma was changed in response to fluctuation in the blood insulin levels. In plasma under the physiologic conditions, there is an insufficient amount of reduced glutathione to elicit the insulin degrading activity, but in the liver there is a sufficient amount of reduced glutathione to manifest this activity. This evidence further supports the concept that an autoregulatory system of insulin degradation in the liver exists in man.

Autoregulatory system of corticosteroid metabolism in the liver

Abstract The adaptative capacity of the liver to metabolize biologically active corticosteroids associated with fluctuations in their levels in blood was studied in man, treated with ACTH, cortisone, and cortisol. Changes in the rate of metabolism of corticosteroids were inferred from the determinations of excretion of non-metabolized unconjugated and metabolized conjugated corticosteroids. A marked increase in the excretion of conjugated metabolites of 17-hydroxycorticosteroids was observed after the administration of ACTH and cortisone, subcutaneous or oral. The intravenous infusion of cortisol resulted in an increase in the renal creatinine clearance associated with an increased urinary excretion of corticosteroids. Despite the increase in the excretion of metabolites of cortisol in the urine, the blood levels of cortisol metabolites were also markedly increased following the infusion of cortisol, suggesting an increase in the capacity of the liver to metabolize corticosteroids following an increase in their blood levels. The present study, therefore, suggests that the liver possesses an autoregulatory mechanism for the control of the concentration of corticosteroids in blood, changing the rate of metabolism of hormones secondary to fluctuation in their blood levels.

Mode of action of glucocorticoids III. The inhibition of amino acid incorporation by thymus subcellular fractions in vitro following administration of triamcinolone

Abstract 1. 1. The effect of the glucocorticoid triamcinolone observed within 2 to 4 h after subcutaneous injection on the incorporation of 14 C-labeled amino acids into proteins of nuclei, mitochondria, and microsomes in the liver and the thymus glands of rats were studied in vitro . 2. 2. The administration of triamcinolone (350 μg per 100 g of body weight) to fed rats inhibited labeled amino acid incorporation into the proteins of isolated thymus nuclei, mitochondria, and microsomes, whereas amino acid incorporation into the proteins of hepatic mitochondria and microsomes was not modified.

Corticosteroid determination in cerebrospinal fluid

Abstract An attempt was made to determine the levels of corticosteroids in cerebrospinal fluid, in order to study the role of adrenal cortical hormones in the central nervous system in various clinical conditions. The concentration of adrenal cortical hormones in cerebrospinal fluid is so low that the determination of 17 hydroxycorticosteroids in small volumes of cerebrospinal fluid by a method employing the phenylhydrazine reaction is difficult. In this investigation, a simple fluorometric technic was used for the determination of corticosteroids in small quantitities of cerebrospinal fluid. This method offers adequate sensitivity and accuracy for the measurement of normal or elevated levels of corticosteroids in human cerebrospinal fluid.

Study of mechanism of autoregulatory system of corticosteroid metabolism in liver.

Abstract A direct correlation between the elevation of blood levels of corticosteroids and the increase in the metabolism of corticosteroids by the liver was observed in vitro and in vivo. The mechanism of this auto-regulatory system of corticosteroid metabolism by the liver, secondary to fluctuation of their blood levels, was studied. The rate of corticosteroid metabolism in the liver was greater at higher levels of nonprotein-bound corticosteroids in serum than that obtained at lower levels. This suggests an important role of the activity of steroid hydrogenases in this regulatory system. In addition, the serum protein binding of corticosteroids plays a role in this regulatory system. The nonprotein-bound corticosteroids in serum were more rapidly metabolized in the liver than the protein-bound corticosteroids. Under the physiologic conditions where the total steroid level in serum was below the binding capacity of serum protein, at lower corticosteroid levels a proportionally greater amount of corticosteroids in the blood was bound to serum protein, and relatively less available to the liver for metabolism than would obtain at higher corticosteroid levels. Thus, the serum protein binding of corticosteroids plays a role in the regulation of corticosteroid metabolism in the liver. An autoregulatory system of corticosteroid metabolism in the liver plays a role in controlling the concentration of blood corticosteroids supplementary to the control by the regulation of adrenal cortical secretion.

The effect of the administration of cortisol on the levels of cortisol and electrolytes in blood and cerebrospinal fluid in man

Abstract In some patients with brain tumor, neurosurgery involving ventricular drainage and ventriculography resulted in an increase in the sodium level in cerebrospinal fluid without any modification of its level in blood. In these patients, the effects of the administration of cortisol on the levels of corticosteroids, sodium, and potassium in blood and cerebrospinal fluid were studied. After the administration of cortisol, the corticosteroid levels in blood and cerebrospinal fluid were markedly increased. When patients had normal levels of sodium in cerebrospinal fluid, cortisol administration did not affect these sodium levels. However, when the sodium level in cerebrospinal fluid was high, the sodium level decreased 2 to 4 hr after the administration of cortisol. In all these patients, the sodium and potassium levels in blood were not influenced by cortisol administration. This finding may have bearing upon the apparent beneficial action of adrenal cortical hormones on cerebral edema following trauma or brain surgery.