Glucocorticoid receptor IB: mediator of anti-inflammatory and teratogenic functions of both glucocorticoids and phenytoin.
We studied the glucocorticoid receptor complexes of pulmonary and thymic cytosols of female A/J and CD-1 mice and of hepatoma G2 cells by two column-chromatographic systems, using both [3H]dexamethasone (DEX) and [3H]phenytoin (DPH) as ligands. Three DNA-cellulose adsorbable [3H]DEX-receptor complexes were separated in each system. Molecular sieving gave a 7-, a 5.4-, and a 3.5-nm complex (Stokes radii), and DEAE-Sephadex A-50 chromatography gave a complex eluting in the wash, one at 0.14 M KCl, and one at 0.20 M KCl by a KCl gradient. DPH blocked the binding of the 7- and 3.5-nm, wash, and 0.14 M KCl [3H]DEX complexes. Only two DNA-cellulose adsorbable [3H]DPH complexes, each blocked by DEX, were obtained in each system: a 7- and a 3.5-nm, a wash, and a 0.14 M KCl complex. Thus, there is a common receptor for both DPH and DEX. This receptor has two properties which distinguish it from the 5.4-nm DEX-specific receptor: (i) it binds with a variety of steroids other than glucocorticoids and DPH, and (ii) it rebinds new [3H]DEX or [3H]DPH after loss of ligand during chromatographic separation. These results indicate that DPH binds to receptor IB and not to receptor II of Litwack. [G. Litwack, 1976, in Glutathion: Metabolism and Function (Arias, I.M., and Jakoby, W.B., eds.), pp. 285-299, Raven Press, New York]. We have also found that hepatoma G2 cells have only receptor II. DPH affects neither the induction of tyrosine aminotransferase by DEX nor the basal level of this enzyme in these cells. Moreover, neither DEX nor DPH inhibits the release of [3H]arachidonic acid prelabeled in these cells, as they do in thymocytes which have the common receptor. Thus, it appears that glucocorticoid receptor IB binds DEX and DPH as glucocorticoid agonists mediating the anti-inflammatory and teratogenic action of these drugs, while receptor II apparently is responsible for the induction of tyrosine aminotransferase by DEX.
Katsumata
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Gupta
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Goldman
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D000818:Animals; D000893:Anti-Inflammatory Agents; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002850:Chromatography, Gel; D002852:Chromatography, Ion Exchange; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology* / Q000633:toxicity; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D010672:Phenytoin / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D011869:Radioligand Assay; D011965:Receptors, Glucocorticoid / Q000145:classification / Q000502:physiology*; D013723:Teratogens; D013950:Thymus Gland / Q000378:metabolism; D014444:Tyrosine Transaminase / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D013723:Teratogens; D016718:Arachidonic Acid; D010672:Phenytoin; D003907:Dexamethasone; D014444:Tyrosine Transaminase