INVESTIGADORES
GALIGNIANA Mario Daniel
artículos
Título:
The glucocorticoid properties of the synthetic steroid pregna-1,4-diene-11beta-ol-3,20-dione (deltaHOP) are not entirely correlated with the steroid binding to the glucocorticoid receptor.
Autor/es:
VICENT GP, PECCI A, GHINI AA, PIWIEN-PILIPUK G, VELEIRO AS, BURTON G, LANTOS CP, GALIGNIANA MD
Revista:
MOLECULAR AND CELLULAR ENDOCRINOLOGY.
Editorial:
ELSEVIER IRELAND LTD
Referencias:
Lugar: Amsterdam; Año: 1999 vol. 149 p. 207 - 219
ISSN:
0303-7207
Resumen:
The natural steroid 11beta-hydroxyprogesterone is not only a modulator
of 11beta-hydroxy-steroid dehydrogenase activity, but also an efficient
inducer of tyrosine aminotransferase activity in hepatocytes. In
contrast with the low affinity for the mineralocorticoid receptor.
11beta-hydroxyprogesterone binds well to both the glucocorticoid
receptor and the carrier protein transcortin. It is accepted that the
introduction of a 1:ene double bond into 3-keto 4:ene steroids increases
the glucocorticoid potency, so that 3-keto-1,4:diene steroids show
improved chemical stability and are more potent glucocorticoids than
their respective 4:ene analogs. The steroid
pregna-1,4-diene-11beta-ol-3,20-dione (deltaHOP) had previously been
described as an anti-inflamatory compound and an inhibitor of
macromolecular biosynthesis in thymocytes and lymphocytes. In such
studies, deltaHOP also exhibited some particular glucocorticoid
properties which made it attractive as a tool for the study of the
mechanism of action of glucocorticoids. In the present paper we show
that deltaHOP possesses some classical biological actions of
glucocorticoids such as deposition of glycogen in rat liver, induction
of TAT activity in hepatocytes, and inhibition of the uptake of leucine
and thymidine by thymocytes. It also exhibits minimal sodium-retaining
properties. Consistent with these biological effects, deltaHOP shows a
70 times lower relative binding affinity for the mineralocortioid
receptor than aldosterone, but a reasonable affinity for the
glucocorticoid receptor, and is as efficient as dexamethasone in
dissociating the 90 kDa heat shock protein from the glucocorticoid
receptor heterocomplex. However, the inhibition of the uptake of amino
acids and nucleotides observed in the presence of deltaHOP is not
efficiently blocked when thymocytes are coincubated in the presence of
steroids with known antiglucocorticoid activity. deltaHOP is similarly
inefficient in inducing chloramphenicol-acetyl transferase activity in
cells transfected with a plasmid that possesses two canonical
glucocorticoid-responsive elements. Unlike most glucocorticoids,
deltaHOP does not induce the fragmentation of DNA in a regular pattern
characteristic of apoptosis and it does not reduce thymus weight. This
unusual dissociation of glucocorticoid parameters makes deltaHOP a
useful tool to discriminate between mechanisms of action by which
steroids can exert their biological effects.