This project is concerned with signals responsible for changes in expression and transport function of ATP-driven, xenobiotic efflux pumps (Mrp2, Mrp4, BCRP and p-glycoprotein) in renal proximal tubule. We use comparative models (single, intact proximal tubules from teleost fish, mammalian renal slices, and renal cells in culture) in combination with confocal microscopy to follow the transport of fluorescent drugs through the renal tubule epithelium and into the urinary space. Thus, we are able to identify the physiologically relevant extracellular signals (hormones, metabolites, xenobiotics), the affected transporters and the intracellular signaling pathways that modulate xenobiotic excretion in proximal tubule. Recent experiments have identified two additional modes of transporter regulation in renal proximal tubules. First, ligands of the aryl hydrocarbon receptor (AhR) upregulate P-glycoprotein, Mrp2 and BCRP expression over a period of hours. This appears to be a protective mechanism through which polycyclic aromatics, including dioxin, at very low levels, act through the aryl hydrocarbon receptor, (AhR) to induce expression and increase transport activity of three ABC transporters that are xenobiotic efflux pumps, P-glycoprotein, Mrp2 and Bcrp. Such induction has the potential to alter the pharmacokinetics of therapeutic drugs and thus alter their efficacy/toxicity profile. Our recent experiments show that a similar regulatory mechanism is active in other barrier and excretory tissues. Second, activation of the glucocorticoid receptor (GR) with both synthetic and endogenous glucocorticoids rapidly increases Mrp2-mediated transport in renal proximal tubules. Glucocorticoids act through a non-genomic mechanism involving tyrosine kinase-based signaling through cMet. This signaling from GR to the transporter could underlie drug-drug interactions at the level of renal efflux, reducing plasma levels of toxicants (a plus) and of therapeutics (a problem).
| Prevoo, Brigitte; Miller, David S; van de Water, Femke M et al. (2011) Rapid, nongenomic stimulation of multidrug resistance protein 2 (Mrp2) activity by glucocorticoids in renal proximal tubule. J Pharmacol Exp Ther 338:362-71 |
