Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2006) 11 S48

ECE2006 Symposia How hormones get into cells (4 abstracts)

Multidrug resistance P-glycoprotein (mdr-1) excluding corticosteroids from brain

ER de Kloet


LACDR/LUMC, Leiden, 2300RA, Netherlands.


In rodents synthetic glucocorticoids such as e.g. dexamethasone poorly penetrate the blood brain barrier because of multidrug resistance P-glycoprotein (mdr-Pgp). Also cortisol, not naturally occurring in rats and mice, is hampered in uptake. The evidence for this role of the efflux transporter was substantiated with the mdr1a knock out mice. 3H- cortisol and 3H-dexamethasone administered to the mdr1a mutants did label brain targets that retained the steroids poorly in the wild types. Also in human brain cortisol rather than corticosterone was hampered in brain penetration as judged from steroid profiles generated with Liquid Chromatography-tandem Mass Spectrometry in post mortem samples. These findings were confirmed with monolayers of epithelial cells stably expressing human mdr-Pgp. Interestingly,in this cell system the glucocorticoid antagonist mifepristone blocked Pgp-mediated cortisol transport suggesting that in vivo such antagonists actually facilitate steroid uptake in the brain. From functional perspective the findings reinforce the notion that moderate doses of dexamethasone block stress-induced hypothalamic-pituitary-adrenal (HPA) activation primarily at the level of the anterior pituitary. As a consequence the secretion of endogenous corticosterone is suppressed. While peripherally the lack of corticosterone is substituted for by dexamethasone, this is not the case in the brain. Indeed In animals subchronically treated with dexamethasone CRH mRNA and hnRNA expressions were enhanced in the PVN, while stress-induced c-fos mRNA showed resistance to suppression. The results support the concept that low doses of dexamethasone can create a hypocorticoid state in the brain. Supported by the Royal Netherlands Society for Arts and Sciences.

Volume 11

8th European Congress of Endocrinology incorporating the British Endocrine Societies

European Society of Endocrinology 
British Endocrine Societies 

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