An inhibitor of ornithine decarboxylase in the thymus and spleen of dexamethasone-treated rats

Abstract

A marked decrease in activity of ornithine decarboxylase in thymus and spleen occurs soon after treatment of rats with a glucocorticoid. In the present study, evidence was obtained that extracts of these tissues prepared 5 h after administration of dexamethasone, when the enzyme activity is very low, contain an inhibitor of ornithine decarboxylase. The inhibitor is also present at 12 h after treatment and, in lesser amount, at 2.5 h, but was not evident at 24 h. The inhibitory activity was destroyed by treatment with heat or with trypsin, and was not lost on dialysis of the extract. Preliminary experiments indicate that the Mr of the inhibitor is greater than 50 000, which differentiates it from antizyme, an inhibitor of ornithine decarboxylase found in several other cell types. The inhibitor seems to act by a non-catalytic and non-competitive mechanism. The inhibition is dependent on the amount of inhibitor and does not change with time. Since inhibition is not changed by dialysis of the inhibitory extract, its activity apparently does not require small-Mr substances. This differentiates it from inhibitors which inactivate ornithine decarboxylase by covalent modification, such as the polyamine-dependent protein kinase or transglutaminase. The formation of this inhibitor is an early event in lymphoid tissues in response to dexamethasone and may be important in causing the inhibition of cell division which precedes the destruction of lymphocytes.

Changes in ornithine decarboxylase and antizyme activities in developing mouse brain

“…(2) its inhibitory effect on ODC can be reversed by antizyme inhibitor; (3) its Mr (26000) agrees reasonably with reported values for antizymes from a variety of sources, such as rat liver (Heller et al, 1976;Fujita et al, 1984;Kitani & Fujisawa, 1984), mouse kidney (Hayashi et al, 1986), H-35 cells (Fong et al, 1976), L-1210 and mouse neuroblastoma cells (Heller et al, 1976), RK13 rabbit kidney cells (Murakami et al, 1986) and rat lymphoma cells (Richards et al, 1986), although antizymes of Mr 50000-90000 have also been found in rat thymus (Bishop et al, 1985), rat mammary gland (Hu & Brosnan, 1987) and rat lymphoma cells (Richards et al, 1986). Although we did not examine another important criterion for antizyme, namely its inducibility by polyamines (Fong et al, 1976), Laitinen et al (1985b) observed that intraventricular administration of spermine caused some increase in the amounts of free and total antizyme activities in mouse brain.…”

Rapid and regulated degradation of ornithine decarboxylase

“…Thus, antizymes of 50 kDa have been reported to be present in rat thymus [150] and mammary gland [151], and even antizyme of 90 kDa was observed in lymphoma cells [152]. Northern-blot analysis indicated that thymus extract contained a single hybridizable antizyme mRNA of a size identical with that of rat liver antizyme mRNA [73].…”

Dexamethasone decreases the spermidine and spermine concentrations and polyamine oxidase activity in rat thymus

“…Earlier results showed that the pharmacological dose of corticosterone or cortisol produced a rapid and significant decrease in ornithine decarboxylase (ODC) and S -adenosyl-L-methionine decarboxylase activities in the thymus of adult rats [48][49][50] . These biosynthetic polyamine decarboxylases are known to be located only in the lymphocytes of the thymus [43] .…”

“…These biosynthetic polyamine decarboxylases are known to be located only in the lymphocytes of the thymus [43] . A marked decrease in ODC activity in the thymus and spleen occurs soon after administration of dexamethasone to rats [49][50][51] . The formation of an ODC inhibitor is an early event in lymphoid tissues in response to dexamethasone, causing the marked decrease of ODC activity, which may be the important reason for the inhibition of cell division that precedes the destruction of lymphocytes [19, 48 -51] .…”