Modulation of ABC Transporters by Nuclear Receptors. Physiological, Pathological and Pharmacological Aspects.

ABC transporters are membrane proteins mediating the efflux of endo- and xenobiotics. Transporter expression is not static but instead is subject to a dynamic modulation aiming at responding to changes in the internal environment and thus at maintaining homeostatic conditions. Nuclear receptors are ligand modulated transcription factors that get activated upon changes in the intracellular concentrations of the respective agonists and bind to response elements within the promoter of ABC transporters, thus modulating their expression and, consequently, their activity. This review compiles information about transporter regulation by nuclear receptors classified according to the perpetrator compounds and the biological effects resulting from the regulation. Modulation by hormone receptors is involved in maintaining endocrine homeostasis and may also lead to an altered efflux of other substrates in cases of altered hormonal levels. Xenobiotic receptors play a key role in limiting the accumulation of potentially harmful compounds. In addition, their frequent activation by therapeutic agents makes them common molecular elements mediating drug-drug interactions and cancer multidrug resistance. Finally, lipid and retinoid receptors are usually activated by endogenous molecules, thus sensing metabolic changes and inducing ABC transporters to counteract potential alterations. Furthermore, the axis nuclear receptor-ABC transporter constitutes a promising therapeutic target for the treatment of several disease states like cancer, atherosclerosis and dyslipidemia. In the current work, we summarize the information available on the pharmacological potential of nuclear receptor modulators and discuss their applicability in the clinical practice.