Hepatic transporters – Regulation, induction and potential for drug-drug interactions

Abstract

Event Abstract Back to Event Hepatic transporters – Regulation, induction and potential for drug-drug interactions Gabrielle Hawksworth1* 1 University of Aberdeen, Department of Molecular Toxicology, United Kingdom Organic anion transporting polypeptides (Oatps) are basolateral membrane solute carriers with a broad range of substrates, including bile salts, steroid conjugates, thyroid hormones and numerous drugs. The three predominant Oatps in rat liver are Oatp1a1, Oatp1a4 and Oatp1b2. Nuclear receptors, including the pregnane X receptor (PXR), constitutive androstane receptor (CAR) and farnesoid X receptor (FXR) are implicated in the regulation of both transporters and P450s. In vivo dosing of rats with 150mg/kg dexamethasone for 72h caused a 50 fold induction of Oatp1a4 expression, whilst having no significant effect on the expression of Oatp1a1 or Oatp1b2. Treatment of sandwich cultured hepatocytes with PXR agonists, dexamethasone or pregnenolone-16 α-carbonitrile, induced expression of Oatp1a4 6-8 fold. As was seen in vivo, treatment with PXR agonists did not significantly affect expression of Oatp1a1 or Oatp1b2. The FXR agonists, GW-4064 and chenodeoxycholic acid, caused a dose-dependent decrease in the expression levels of Oatps. The role of PXR in the induction of Oatp1a4 by dexamethasone and PCN was confirmed by transfection of cells with PXRsiRNA prior to treatment with PCN. The ATP-dependent multidrug resistance associated proteins (Mrps/Abccs) are responsible for the efflux of a wide range of substrates, including glutathione, glucuronide and sulphate conjugates, unconjugated organic anions and bile salts. Abccs 1-6 are expressed in rat and human livers, although only Abcc2 is located on the apical membrane. Sandwich culture is essential for promoting bile canalicular reformation in vitro and for the expression and function of the abccs. PXR, CAR and FXR agonists are involved in the induction of abcc2 and abcc3. Abcc2 and 5 are upregulated in response to a toxic insult to the cell, probably via Nrf2 activation, suggesting a role in cell defence. Keywords: Organic anion transporting polypeptides, Oatp1a4, Oatp1a1, Oatp1b2, Abccs Conference: 8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010, Thessaloniki, Greece, 1 Oct - 5 Oct, 2010. Presentation Type: Invited speaker Topic: Drug transport Citation: Hawksworth G (2010). Hepatic transporters – Regulation, induction and potential for drug-drug interactions. Front. Pharmacol. Conference Abstract: 8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010. doi: 10.3389/conf.fphar.2010.60.00128 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Oct 2010; Published Online: 04 Nov 2010. * Correspondence: Dr. Gabrielle Hawksworth, University of Aberdeen, Department of Molecular Toxicology, Aberdeen, United Kingdom, g.m.hawksworth@abdn.ac.uk Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Gabrielle Hawksworth Google Gabrielle Hawksworth Google Scholar Gabrielle Hawksworth PubMed Gabrielle Hawksworth Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.