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Title: Regulation of the expression and function of P-glycoprotein by the nuclear xenobiotic receptor PXR
Author: Haslam, lain S.
ISNI:       0000 0001 3544 4590
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2007
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The intestinal expression of P-glycoprotein (Pgp) has recently been recognised to impact on the disposition of a wide range of orally administered drug compounds. From an evolutionary perspective, efflux transporters such as P-glycoprotein may have developed to protect the body from ingested toxins, however the structural promiscuity displayed by Pgp in particular, has also resulted in the recognition of many modem drug compounds. The apical localisation and secretory orientation of this transporter has therefore resulted in the reduced absorption of many of these drugs, such as the cardiac glycoside digoxin, resulting in low or variable oral availability. A range of drug-drug, herb-drug and even food-drug interactions have been identified, resulting from inhibition or induction of P-glycoprotein activity, including the well characterised interactions between the antibiotic rifampin and digoxin (drug-drug) and hyperforin (an active constituent of St John's Wort) and cyclosporine A (herb-drug). The activity of a number of nuclear receptors, responsible for increasing the expression of detoxifying proteins such as Pgp and metabolic enzymes of the cytochrome P450 family, can be attributed to xenobiotic exposure. This includes 2 members of the NRlI family of nuclear receptors, the pregnane X receptor (PXR; NRII2) and constitutive androstane receptor (CAR; NR1I3), both of which have been designated the role of 'xenosensor'. Pgp expression is believed to increase along the proximal-distal axis of the mammalian intestine, although the regional inductive capacity is unknown. Here we have determined significant increases in Pgp expression and secretory activity (as determined by eH]-digoxin efflux) in the distal rat intestine, resulting from treatment with the rodent PXR activator PCN. It appears that reduced digoxin plasma concentrations result from an interplay between increased hepatic accumulation, biliary excretion and distal intestinal secretion. In order to study inductive interactions in a human system, the human intestinal adenocarcinoma cell line T84 was identified as a suitable in vitro model, expressing both MDRI and PXR, as well as displaying the epithelial characteristics (polarised expression and the formation of tight monolayers) that allow physiologically relevant bi-directional transport assays, utilising digoxin as a model Pgp substrate. T84 cells were found to respond to the PXR activator rifampin, resulting in the increased expression and function of Pgp. Digoxin ireatment also greatly increased MDRI expression and Pgp efflux activity, although this effect appears to be distinct from that of rifampin, based on the differential impact on PXR and CAR expression. Furthermore, the T84 cell line was found to lend itself to high-throughput analysis, with a range of structurally and functionally diverse drug compounds impacting on the expression and function of Pgp, as well as modulating levels of the nuclear receptors themselves.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available