title: Differential effect of glucocorticoid receptor antagonists on glucocorticoid receptor nuclear translocation and DNA binding.
abstract: The effects of RU486 and S-P, a more selective glucocorticoid receptor antagonist from Schering-Plough, were investigated on glucocorticoid receptor nuclear translocation and DNA binding. In the in vitro study, AtT20 cells were treated with vehicle or with RU486, S-P or corticosterone (3-300 nM) or co-treated with vehicle or glucocorticoid receptor antagonists (3-300 nM) and 30 nM corticosterone. Both glucocorticoid receptor antagonists induced glucocorticoid receptor nuclear translocation but only RU486 induced DNA binding. RU486 potentiated the effect of corticosterone on glucocorticoid receptor nuclear translocation and DNA binding, S-P inhibited corticosterone-induced glucocorticoid receptor nuclear translocation, but not glucocorticoid receptor-DNA binding. In the in vivo study, adrenalectomized rats were treated with vehicle, RU486 (20 mg/kg) and S-P (50 mg/kg) alone or in combination with corticosterone (3 mg/kg). RU486 induced glucocorticoid receptor nuclear translocation in the pituitary, hippocampus and prefrontal cortex and glucocorticoid receptor-DNA binding in the hippocampus, whereas no effect of S-P on glucocorticoid receptor nuclear translocation or DNA binding was observed in any of the areas analysed. These findings reveal differential effects of RU486 and S-P on areas involved in regulation of hypothalamic-pituitary-adrenal axis activity in vivo and they are important in light of the potential use of this class of compounds in the treatment of disorders associated with hyperactivity of the hypothalamic-pituitary-adrenal axis.
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK. f.spiga@bristol.ac.uk
authors.forename: Francesca
authors.initials: F
authors.lastname: Spiga
authors.forename: David M
authors.initials: DM
authors.lastname: Knight
authors.forename: Susanne K
authors.initials: SK
authors.lastname: Droste
authors.forename: Becky
authors.initials: B
authors.lastname: Conway-Campbell
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kershaw
authors.forename: Cliona P
authors.initials: CP
authors.lastname: MacSweeney
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Thomson
authors.forename: Mark
authors.initials: M
authors.lastname: Craighead
authors.forename: Bernard W M M
authors.initials: BW
authors.lastname: Peeters
authors.forename: Stafford L
authors.initials: SL
authors.lastname: Lightman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004357:Drug Synergism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D015735:Mifepristone / Q000031:analogs & derivatives / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D004247:DNA; D003345:Corticosterone