title: ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy.
abstract: The aim of treatment in congenital adrenal hyperplasia is to suppress excess adrenal androgens while achieving physiological glucocorticoid replacement. However, current glucocorticoid replacement regimes are inadequate because doses sufficient to suppress excess androgens almost invariably induce adverse metabolic effects. Although both cortisol and corticosterone are glucocorticoids that circulate in human plasma, any physiological role for corticosterone has been neglected. In the brain, the adenosine 5'-triphosphate-binding cassette transporter ABCB1 exports cortisol but not corticosterone. Conversely, ABCC1 exports corticosterone but not cortisol. We show that ABCC1, but not ABCB1, is expressed in human adipose and that ABCC1 inhibition increases intracellular corticosterone, but not cortisol, and induces glucocorticoid-responsive gene transcription in human adipocytes. Both C57Bl/6 mice treated with the ABCC1 inhibitor probenecid and FVB mice with deletion of Abcc1 accumulated more corticosterone than cortisol in adipose after adrenalectomy and corticosteroid infusion. This accumulation was sufficient to increase glucocorticoid-responsive adipose transcript expression. In human adipose tissue, tissue corticosterone concentrations were consistently low, and ABCC1 mRNA was up-regulated in obesity. To test the hypothesis that corticosterone effectively suppresses adrenocorticotropic hormone (ACTH) without the metabolic adverse effects of cortisol, we infused cortisol or corticosterone in patients with Addison's disease. ACTH suppression was similar, but subcutaneous adipose transcripts of glucocorticoid-responsive genes were higher after infusion with cortisol rather than with corticosterone. These data indicate that corticosterone may be a metabolically favorable alternative to cortisol for glucocorticoid replacement therapy when ACTH suppression is desirable, as in congenital adrenal hyperplasia, and justify development of a pharmaceutical preparation.
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Nixon
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mackenzie
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Taylor
authors.affiliation: Mass Spectrometry Core Laboratory, Edinburgh Clinical Research Facility, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Natalie Z M
authors.initials: NZ
authors.lastname: Homer
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK. Centre for Integrative Physiology, Hugh Robson Building, George Square, University of Edinburgh, Edinburgh EH8 9XD, UK.
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Livingstone
authors.affiliation: Institute for Bioengineering, School of Engineering, University of Edinburgh, Edinburgh EH9 3DW, UK.
authors.forename: Rabah
authors.initials: R
authors.lastname: Mouras
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK. Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH25 9RG, UK.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Morgan
authors.affiliation: Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Mole
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Roland H
authors.initials: RH
authors.lastname: Stimson
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Reynolds
authors.affiliation: Institute for Bioengineering, School of Engineering, University of Edinburgh, Edinburgh EH9 3DW, UK.
authors.forename: Alistair P D
authors.initials: AP
authors.lastname: Elfick
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK. Mass Spectrometry Core Laboratory, Edinburgh Clinical Research Facility, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Andrew
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK. b.walker@ed.ac.uk.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
mesh_terms: D000224:Addison Disease / Q000188:drug therapy; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors; D000818:Animals; D001693:Biological Transport, Active; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003345:Corticosterone / Q000378:metabolism / Q000494:pharmacology*; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D057170:Translational Research, Biomedical
chemical_list: D000324:Adrenocorticotropic Hormone; D003345:Corticosterone; D005938:Glucocorticoids; D006854:Hydrocortisone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C421109:multidrug resistance-associated protein 1