Research ArticleMetabolism

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

Science Translational Medicine  17 Aug 2016:
Vol. 8, Issue 352, pp. 352ra109
DOI: 10.1126/scitranslmed.aaf9074

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A kinder, gentler steroid

In some clinical situations, such as congenital adrenal hyperplasia, it is necessary to suppress endogenous adrenal function by blocking the secretion of the adrenocorticotropic hormone from the brain. Usually, cortisol is used for this purpose, but cortisol doses large enough to achieve adrenal suppression are problematic because they cause metabolic adverse effects. Nixon et al. have identified another steroid, corticosterone, as offering a better solution for this treatment scenario. Because of the differences in the expression patterns of transporters that export each steroid out of cells, corticosterone is more effectively retained in brain cells, where it is needed, and less likely to be retained in adipose tissue, where it would cause side effects.

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.

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