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ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy

Lookup NU author(s): Professor Brian Walker

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Association for the Advancement of Science, 2016.

For re-use rights please refer to the publisher's terms and conditions.


Abstract

© 2016 American Association for the Advancement of Science. All rights Reserved. The aim of treatment in congenital adrenal hyperplasia is to suppress excess adrenal androgenswhile 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 inhuman adipocytes. Both C57Bl/6mice 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 themetabolic 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.


Publication metadata

Author(s): Nixon M, Mackenzie SD, Taylor AI, Homer NZM, Livingstone DE, Mouras R, Morgan RA, Mole DJ, Stimson RH, Reynolds RM, Elfick APD, Andrew R, Walker BR

Publication type: Article

Publication status: Published

Journal: Science Translational Medicine

Year: 2016

Volume: 8

Issue: 352

Print publication date: 17/08/2016

Acceptance date: 29/06/2016

Date deposited: 11/11/2020

ISSN (print): 1946-6234

ISSN (electronic): 1946-6242

Publisher: American Association for the Advancement of Science

URL: https://doi.org/10.1126/scitranslmed.aaf9074

DOI: 10.1126/scitranslmed.aaf9074


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