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dc.contributor.advisorAlcorn, Janeen_US
dc.creatorGill, Puneeten_US
dc.date.accessioned2013-04-06T12:00:18Z
dc.date.available2013-04-06T12:00:18Z
dc.date.created2013-03en_US
dc.date.issued2013-04-05en_US
dc.date.submittedMarch 2013en_US
dc.identifier.urihttp://hdl.handle.net/10388/ETD-2013-03-947en_US
dc.description.abstractIntravenous feeding of patients with essential and balanced nutrition is required when enteral feeding is not tolerated, therefore indicating the need for Total Parenteral Nutrition (TPN). This life-saving therapy is also associated with the increase risk of intrahepatic cholestasis. The incidence of TPN-related hepatobiliary complications is common in both adults and infants on TPN. Previous work in in vivo models suggested that one of the potential contributing factors is the aluminum contamination of TPN solutions. The mechanism by which aluminum contributes to the PNAC development, though, was unknown. Aluminum as a risk factor may influence a number of hepatocellular functions to lead to cholestasis but one possible mechanism is the potential for aluminum to cause dysfunction of those transporters responsible in the maintenance of bile flow. To provide some initial information regarding the role of aluminum as a contributing factor to cholestasis and the possible underlying mechanism, cytotoxicity studies were conducted to determine whether aluminum causes direct toxicity of HepG2 cells. Furthermore, the influence of aluminum on the mRNA expression of hepatic biliary transporters (BSEP, MRP2, MATE1, NTCP) and nuclear transcription factor (FXR) in HepG2 cells using real-time RT-PCR analysis was assessed. Since inflammation is a component of cholestasis, these investigations also involved the use of an inflammatory stimulus, lipopolysaccharide (LPS), to determine whether the effects of aluminum were exacerbated by underlying inflammation. My data suggest that for the canalicular hepatic transporters MATE1 and BSEP, aluminum at higher concentration alone as well as with LPS caused increased mRNA expression levels. In addition to this, BSEP mRNA expression was preserved and that of MATE1 was increased on LPS exposure. Given the particular importance of BSEP in the maintenance of bile flow and reported effects of drug-induced inhibition of BSEP to cause hepatic cholestasis, the influence of aluminum on BSEP (and MATE1) protein expression and activity warrant investigation. Further studies may identify that inhibition of BSEP function (and possibly MATE1) by aluminum contamination of total parenteral nutrition formulations may explain, in part, the intrahepatic cholestasis associated with parenteral nutrition.en_US
dc.language.isoengen_US
dc.subjectAluminumen_US
dc.subjectParenteral Nutrition Associated Cholestasisen_US
dc.subjectHepatic biliary Transportersen_US
dc.subjectInflammationen_US
dc.titleTHE EFFECT OF ALUMINUM ON HEPATIC BILIARY TRANSPORTERS AS A CONTRIBUTING FACTOR TO PARENTERAL NUTRITION INDUCED INTRAHEPATIC CHOLESTASISen_US
thesis.degree.departmentPharmacy and Nutritionen_US
thesis.degree.disciplinePharmacyen_US
thesis.degree.grantorUniversity of Saskatchewanen_US
thesis.degree.levelMastersen_US
thesis.degree.nameMaster of Science (M.Sc.)en_US
dc.type.materialtexten_US
dc.type.genreThesisen_US
dc.contributor.committeeMemberZello, Gordon A.en_US
dc.contributor.committeeMemberKrol, Eden_US


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