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

Abstract

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.

Acquired ABC-transporter overexpression in cancer cells: transcriptional induction or Darwinian selection?

“…There, they bind to their receptor-specific xenobiotic response elements or hormone response elements at the promoter regions of their specific target genes (Tukey and Strassburg 2000 ; Mangelsdorf et al 1995 ; Evans and Mangelsdorf 2014 ). The pregnane-x-receptor (PXR) is probably the most prominent NR known to induce MDR (Chen and Nie 2009 ; Rigalli et al 2019 ). It binds a wide variety of endogenous or exogenous compounds such as hormones, drugs, food additives, and pollutants.…”

Sex-, feeding-, and circadian time-dependency of P-glycoprotein expression and activity - implications for mechanistic pharmacokinetics modeling

“…P-gp , like many transporters, is regulated by nuclear receptors, such as C-androstane receptors, that are in turn regulated by circadian clock-controlled transcription factors 15 . The mammalian circadian timing system (CTS) involves a hierarchical network of molecular clocks that reside within each cell and are coordinated by the suprachiasmatic nuclei (SCN), a hypothalamic pacemaker, that can be entrained to exactly 24 h by external cues.…”

Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells

“…On the contrary, our results show a significant up-regulation of P-gp expression and activity by NMGA in two hepatic cell lines (Fig 1a and b). In this regard, an increase in the expression and activity of P-gp has been already related to several, in part life-threatening, drug-drug interactions [8,40,41]. For instance, healthy volunteers treated with rifampicin exhibited increased hepatic P-gp expression with higher biliary excretion of digoxin and concomitant reduction in its C max and AUC [42].…”

“…Other drug-drug interactions have been reported, for instance, for the MRP3 substrate acetaminophen-glucuronide [6] and the BCRP substrate methotrexate [7]. In general, most of the reported cases of ABC transporter regulation by drugs can be explained in terms of activation of nuclear receptors or transcription factors as well as post-transcriptional mechanisms finally impacting in the expression levels of the different transporters [8,9]. Nomegestrol acetate (NMGA) is a potent synthetic progestogen originally used alone for treatment of uterine disorders or in combination with estradiol (E2) as hormonal replacement therapy in postmenopausal women.…”