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 ATP-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 upregulated in obesity. To test the hypothesis that corticosterone effectively suppresses 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 was higher after cortisol than 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. 48

Residual endogenous corticosteroid production in patients with adrenal insufficiency

“…In agreement with this, Nixon and co-workers have shown that corticosterone rather than cortisol may be the primary glucocorticoid for the brain, as a consequence of tissue-specific expression of transmembrane exporters of corticosteroids. 24 In addition, Schweitzer found that 11-deoxycortisol to cortisol ratios were different in depressed patients when compared to normal volunteers. 25 The use of 11-deoxycortisol may be of potential interest in sev- for assessing residual cortisol secretion.…”

Multi-year longitudinal profiles of cortisol and corticosterone recovered from baleen of North Atlantic right whales (Eubalaena glacialis)

“…cortisol and corticosterone may respond differentially to different types of stressors and might even trigger different downstream responses in target tissues. The two hormones have differing affinities for corticosteroid binding globulin, transporters and receptors (Funder, 2013;MacKenzie, 2015;Nixon et al, 2016;Sacta et al, 2016). In some species, cortisol is a better index of acute stress than corticosterone, while corticosterone can sometimes show stronger relationships to chronic stress (Gong et al, 2015, mouse, Mus musculus;Hancock, 2010, human, Homo sapiens, and guinea pig, Cavia porcellus;MacKenzie, 2015, human;McCorkell et al, 2013, bison, Bison bison;Vera et al, 2011, tucotuco, Ctenomys talarum).…”

The impact of maternal obesity in pregnancy on placental glucocorticoid and macronutrient transport and metabolism

“…Key transporters implicated in placental glucocorticoid transfer include permeability glycoprotein (encoded by ABCB1), breast cancer resistance protein (encoded by ABCG2) and the multidrug resistance associated protein-1 (encoded by ABCC1) [48]. ABCC1 exports corticosterone (not cortisol) and is predominantly localised on the fetal facing BM [49,50].…”