Abstract
BackgroundCortisol 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. MethodsA 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). ResultsDuring 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. ConclusionsAlthough 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.
Highlights
Glucocorticoids play a major role in carbohydrate, protein and lipid metabolism and have significant anti-inflammatory and immunologicalAbbreviations: 11β-hydroxysteroid dehydrogenase enzymes (11βHSDs), 11β-hydroxysteroid dehydrogenase; ATPbinding cassette (ABC), ATP-binding cassette transporters;; ABCB1, ABC transporter B1; ABCC1, ABC transporter C1; Adipose tissue blood flow (ATBF), adipose tissue blood flow; Forearm blood flow (FBF), forearm blood flow; GR, glucocorticoid receptor; HPA, hypothalamic pituitary adrenal; mineralocorticoid receptors (MR), mineralocorticoid receptor; RU486, mifepristone; SGBS, Simpson-Golabi-Behmel syndrome; Tracer:tracee ratio (TTR), tracer:tracee ratio.⁎ Corresponding author at: BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK and Translational & Clinical Research Institute, Newcastle University, UK.actions [1]
ABCC1 transcript levels were more abundant in pituitary compared to both hypothalamus and hippocampus (Fig. 7). These data show that ABCC1 inhibition potentiates the activation of the HPA axis which follows combined receptor blockade in humans
We attribute this to preferential expression of ABCC1 over ABCB1 in the human pituitary
Summary
Cortisol and corticosterone both circulate in human plasma and, due to differing export by ATPbinding cassette (ABC) transporters, may exert differential cellular effects. We hypothesised that ABCC1 inhibition increases corticosteroid receptor occupancy by corticosterone but not cortisol in humans. 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. Conclusions: 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
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