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dc.contributor.authorNicholson, Tara Elizabeth.en_US
dc.date.accessioned2014-10-21T12:36:28Z
dc.date.available2014-10-21T12:36:28Z
dc.date.issued2001en_US
dc.identifier.otherAAINQ66639en_US
dc.identifier.urihttp://hdl.handle.net/10222/55767
dc.descriptionPotential mediators involved in the down-regulation of cytochrome P450 enzymes in the brain and liver during a central inflammatory response induced by the endotoxin, lipopolysaccharide (LPS) were investigated. A role for cytokines as mediators of this depression in cytochrome P450 activity in brain and liver is proposed. An in vitro model utilizing cultured astrocytes was used to examine the direct effects of LPS on induced levels of CYP1A activity in these brain-derived cells. Results demonstrated that the acute phase cytokines TNF-alpha and IL-1beta were produced from these cells in response to incubation with LPS and that these same cytokines modulate CYP1A activity in these cells when added exogenously. In addition, substantial levels of nitric oxide were measured in cultures incubated with LPS and blockade of this release partially attenuated the depression in CYP1A activity.en_US
dc.descriptionAdministration of LPS into the lateral ventricle of the brain was used as an in vivo model of central inflammation. CYP1A activity and protein in both brain and liver were depressed in response to this treatment. The administration of the pro-inflammatory cytokines TNF-alpha, IL-1beta, and IFN-gamma directly into the lateral ventricle emulated the effects of LPS on CYP1A activity only in the brain. In contrast, these centrally administered cytokines did not produce a concomitant loss of CYP1A activity in the liver.en_US
dc.descriptionSignificant levels of several cytokines (TNF-alpha, IL-1beta, and IFN-gamma) were produced in the serum of animals following i.c.v. LPS administration. This production of peripheral cytokines by LPS could not be mimicked by the administration of IL-1beta nor TNF-alpha by i.c.v. injection. In addition, peripherally administered cytokines, at concentrations similar to those detected in serum following i.c.v. injection of LPS, were shown to decrease cytochrome P450 activity in liver.en_US
dc.descriptionThese results suggest that induction of cytokines in the brain may play a direct role in the depression of CYP1A activity in the CNS following the administration of LPS into the lateral ventricle. The production of cytokines within the brain does not appear to participate in the signaling process in the brain that leads to the concomitant loss of CYP1A2 activity in the liver. The subsequent production of cytokines in peripheral tissues does however, appear to play a role in the loss of cytochrome P450 in the liver.en_US
dc.descriptionThesis (Ph.D.)--Dalhousie University (Canada), 2001.en_US
dc.languageengen_US
dc.publisherDalhousie Universityen_US
dc.publisheren_US
dc.subjectHealth Sciences, Pharmacology.en_US
dc.subjectBiology, Animal Physiology.en_US
dc.titlePotential mediators of the downregulation of cytochrome P450 during central inflammation.en_US
dc.typetexten_US
dc.contributor.degreePh.D.en_US
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