ABCC1 modulates negative feedback control of the hypothalamic-pituitary-adrenal axis in vivo in humans

• Published in: Metabolism, clinical and experimental clinical and experimental, 2022-03, Vol.128, p.155118-155118, Article 155118
• Main Authors: Kyle, Catriona J., Nixon, Mark, Homer, Natalie Z.M., Morgan, Ruth A., Andrew, Ruth, Stimson, Roland H., Walker, Brian R.
• Format: Article
• Language: English
• Subjects: ABC transporters; Adipose tissue; Adipose Tissue - blood supply; Adipose Tissue - metabolism; Adrenocorticotropic Hormone - blood; Adult; ATP Binding Cassette Transporter, Subfamily B - physiology; Cross-Over Studies; Double-Blind Method; Glucocorticoids; HPA axis; Humans; Hypothalamo-Hypophyseal System - physiology; Male; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - physiology; Muscle, Skeletal - metabolism; Pituitary-Adrenal System - physiology; Skeletal muscle
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2021.155118

Cortisol and corticosterone both circulate in human plasma and, due to differing export by ATP-binding cassette (ABC) transporters, may exert differential cellular effects. ABCB1 (expressed in brain) exports cortisol not corticosterone while ABCC1 (expressed in adipose and skeletal muscle) exports corticosterone not cortisol. We hypothesised that ABCC1 inhibition increases corticosteroid receptor occupancy by corticosterone but not cortisol in humans. A randomised double-blind crossover study was conducted in 14 healthy men comparing placebo and ABCC1 inhibitor probenecid. Blood sampling, including from veins draining adipose and muscle, was undertaken before and after administration of mineralocorticoid receptor antagonist potassium canrenoate and glucocorticoid receptor antagonist mifepristone (RU486). During placebo, systemic plasma cortisol and corticosterone concentrations increased promptly after canrenoate. Cortisol uptake was detected from adipose but not muscle following canrenoate + RU486. Probenecid significantly increased systemic cortisol concentrations, and tended to increase corticosterone and ACTH concentrations, after combined receptor antagonism but had no effects on net glucocorticoid balance in either adipose or muscle. Using quantitative PCR in brain bank tissue, ABCC1 expression was 5-fold higher in human pituitary than hypothalamus and hippocampus. ABCB1 was more highly expressed in hypothalamus compared to pituitary. Although displacement of corticosterone and/or cortisol from receptors in adipose and skeletal muscle could not be measured with sufficient precision to detect effects of probenecid, ABCC1 inhibition induced a greater incremental activation of the hypothalamic-pituitary-adrenal axis after combined receptor blockade, consistent with ABCC1 exporting corticosterone from the pituitary and adding to the evidence that ABC transporters modulate tissue glucocorticoid sensitivity. •Cortisol and corticosterone are glucocorticoids which both circulate in human plasma•They may exert differential cellular effects due to differing export by ABC transporters•ABCB1 (in brain) exports cortisol not corticosterone while ABCC1 (in adipose) exports corticosterone not cortisol•Inhibiting ABCC1 induced greater activation of the HPA axis after combined GR and MR receptor blockade•This adds to the evidence that ABC transporters modulate tissue glucocorticoid sensitivity