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