Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain.

Abstract:

:In the present study, we investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in the control of access of cortisol and corticosterone to the mouse and human brain. [(3)H]Cortisol poorly penetrated the brain of adrenalectomized wild-type mice, but the uptake was 3.5-fold enhanced after disruption of Pgp expression in mdr 1a(-/-) mice. In sharp contrast, treatment with [(3)H]corticosterone revealed high labeling of brain tissue without difference between both genotypes. Interestingly, human MDR1 Pgp also differentially transported cortisol and corticosterone. LLC-PK1 monolayers stably transfected with MDR1 complementary DNA showed polar transport of [(3)H]cortisol that could be blocked by a specific Pgp blocker, whereas [(3)H]corticosterone transport did not differ between transfected and host cells. Determination of the concentration of both steroids in extracts of human postmortem brain tissue using liquid chromatography mass spectrometry revealed that the ratio of corticosterone over cortisol in the brain was significantly increased relative to plasma. In conclusion, the data demonstrate that in both mouse and human brain the penetration of cortisol is less than that of corticosterone. This finding suggests a more prominent role for corticosterone in control of human brain function than hitherto recognized.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Karssen AM,Meijer OC,van der Sandt IC,Lucassen PJ,de Lange EC,de Boer AG,de Kloet ER

doi

10.1210/endo.142.6.8213

subject

Has Abstract

pub_date

2001-06-01 00:00:00

pages

2686-94

issue

6

eissn

0013-7227

issn

1945-7170

journal_volume

142

pub_type

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