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Title: Differential induction of organic anion transporting polypeptides in rat liver
Author: Cowie, David
ISNI:       0000 0004 2672 6862
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2008
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The organic anion transporting polypeptides (OATP/Oatp) are products of the solute carrier organic anion (SLCO/Slco) transporter gene superfamily and constitute a major class of polyspecific membrane solute carriers at the basolateral membrane of hepatocytes.  Alterations in Oatp hepatic drug uptake have the potential to alter the clinical pharmacokinetics, efficacy and safety of a given drug.  Similarly to their regulation of cytochrome P450 enzymes (CYP450) nuclear receptors (NR), such as the pregnane x receptor (PXR) and constitutive androstane receptor (CAR) have been implicated in the transcriptional regulation of Oatps. Dose response experiments were performed using known PXR and CAR activators in male Sprague Dawley rats to ascertain the effects of NR activation on hepatic Oatp expression.  Dexamethasone, pregnenolone-16α-carbonitrile (PCN), 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or Phenobarbital (PB) were administered for 72h and Taqman real time PCR used to quantify transcript levels and Western blots used to quantify transporter proteins.  Only Oatp1a4 displayed responsiveness to NR activation, Oatp1a1 and Oatp1b2 levels are not altered by NR regulation.  Oatp1a4 mRNA and protein levels were only increased by the PXR ligands, dexamethasone and PCN, dexamethasone being the more potent PXR activator compared to PCN.  Dexamethasone resulted in a statistically significant 8-fold induction of Oatp1a4 mRNA with a maximal increase in response occurring at 50mg/kg (12703 ± 1985 copies/ng RNA compared with control 1540 ± 193 copies/ng RNA, p < 0.001). Increasing doss of 100 mg/kg and 150 mg/kg did not result in increased Oatp1a4 levels.  Western blotting showed that dexamethasone and PCN resulted in an increase of Oatp1a4 protein.  The CAR activator, PB, increased Oatp1a4 protein levels; however this is likely to be via a post transcriptional mechanism as there was no concurrent increase in Oatp1a4 mRNA.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Liver cells ; Anions