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The biological mechanisms that determine cell-specific responses to glucocorticoid hormones may overlap with those that are associated with acquired glucocorticoid resistance. Cell and tIssue specificity can be brought about in many different ways. Studies on the brain, an important glucocorticoid target tIssue, may provide examples of regulatory mechanisms underlying response specificity at multiple levels. In this commentary a number of such mechanisms are discussed, with emphasis on regulation of glucocorticoid bio-availability by the efflux transporter P-glycoprotein and on the variable presence of nuclear proteins which modulate or interfere with gluco- and mineralocorticoid receptor-mediated transcription.
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In the present study, we have investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in hampering the access of the synthetic glucocorticoid, prednisolone. In vivo, a tracer dose of [(3)H]prednisolone poorly penetrated the brain of adrenalectomised wild-type mice, but the uptake was more than threefold enhanced in the absence of Pgp expression in mdr1a (-/-) mice. In vitro, in stably transfected LLC-PK1 monolayers the human MDR1 P-glycoprotein was able to transport prednisolone present at a micromolar concentration. A specific Pgp blocker, LY 335979, could block this polar transport of [(3)H]prednisolone. Human Pgp does not transport all steroids, as cortexolone was not transported at all and aldosterone was only weakly transported. The ability of Pgp to export the synthetic glucocorticoid, prednisolone, suggests that uptake of prednisolone in the human brain is impaired, leading to a discrepancy between central and peripheral actions. Furthermore, the ensuing imbalance in activation of the two types of brain corticosteroid receptors may have consequences for cognitive performance and mood.
