부산대학교 도서관

Responses to hormones that act through nuclear receptors are controlled by modulating hormone concentrations not only in the circulation but also within target tissues. The role of enzymes that amplify or reduce local hormone concentrations is well established for glucocorticoid and other lipophilic hormones; moreover, transmembrane transporters have proven critical in determining tissue responses to thyroid hormones. However, there has been less consideration of the role of transmembrane transport for steroid hormones. ATP-binding cassette (ABC) proteins were first shown to influence the accumulation of glucocorticoids in cells almost three decades ago, but observations over the past 10 years suggest that differential transport propensities of both exogenous and endogenous glucocorticoids by ABCB1 and ABCC1 transporters provide a mechanism whereby different tissues are preferentially sensitive to different steroids. This Review summarizes this evidence and the new insights provided for the physiology and pharmacology of glucocorticoid action, including new approaches to glucocorticoid replacement. This Review discusses the ATP-binding cassette (ABC) proteins ABCB1 and ABCC1 and their preferential cellular export of cortisol and corticosterone, respectively. The article also explores the potential to select therapeutic glucocorticoids on the basis of their different tendencies for export to avoid harmful adverse effects. Key points: Humans have two circulating glucocorticoid hormones, cortisol and corticosterone, which diffuse into cells to become transcription factors when bound to their intracellular receptors. The availability of glucocorticoids to interact with their receptors depends not only on their plasma concentration but also on their intracellular concentration, which is modulated by intracellular enzymes and by transmembrane transporters. Glucocorticoids are susceptible to cellular export by membrane transporters from the ABC (ATP-binding cassette) transporter family: cortisol is a substrate for the ABCB1 transporter, and corticosterone for ABCC1. Tissues expressing ABCB1 (such as the brain) might be relatively sensitive to corticosterone over cortisol; those expressing ABCC1, such as adipose, might be more sensitive to cortisol. In future, therapeutic glucocorticoids could be selected on the basis of lower tendency to be exported from sites of efficacy and higher tendency for export from sites where harmful adverse effects occur. [ABSTRACT FROM AUTHOR]