Multidrug resistance P-glycoprotein hampers the access of cortisol but notof corticosterone to mouse and human brain

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 acc ess of cortisol and corticosterone to the mouse and human brain. [H-3] Cortisol poorly penetrated the brain of adrenalectomized wildtype mic e, but the uptake was 3.5-fold enhanced after disruption of Pgp expression in mdr 1a(-/-) mice. In sharp contrast, treatment with [H-3]corticosterone revealed high labeling of brain tissue without difference between both geno types. Interestingly, human MDR1 Pgp also differentially transported cortisol and corticosterone. LLC-PK1 monolayers stably transfected with MDR1 complementa ry DNA showed polar transport of [H-3]cortisol that could be blocked by a s pecific Pgp blocker, whereas [H-3]corticosterone transport did not differ b etween transfected and host cells. Determination of the concentration of both steroids in extracts of human po stmortem brain tissue using liquid chromatography mass spectrometry reveale d that the ratio of corticosterone over cortisol in the brain was significa ntly 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 s uggests a more prominent role for corticosterone in control of human brain function than hitherto recognized.