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dc.contributor.authorBryden, Kathleen Estelle.en_US
dc.date.accessioned2014-10-21T12:35:47Z
dc.date.available2014-10-21T12:35:47Z
dc.date.issued1995en_US
dc.identifier.otherAAINN05190en_US
dc.identifier.urihttp://hdl.handle.net/10222/55030
dc.descriptionCytochrome P450 isoforms and related biotransformations are depressed by agents independently characterized as triggers of systemic inflammation and the hepatic acute phase response (APR). At the time this thesis work was undertaken, the recognition of the role of interleukin-6 (IL-6) as a modulator of hepatic gene expression was in its primary stage of investigation. This work complemented research on interleukin-l and tumor necrosis factor alpha (TNF), known triggers of the hepatic APR, and also produced by the administration of many agents known to produce P450 depression. Recombinant TNF produced a dose- and time-dependent depression of hepatic P450 and related catalysis when administered to mice. This was accompanied by depressed expression of albumin mRNA, an indicator of the phenotypic changes associated with an APR to inflammation. Interleukin-6 administration did not consistently depress P450 in vivo, however, primary murine hepatocytes treated with IL6 exhibited a dose-dependent depression of total P450 and catalysis, demonstrating that P450 regulation is sensitive to the presence of this cytokine. These findings indicate that P450 expression is modulated by the inflammatory cytokines TNF and IL-6, and that this depression occurs concomitantly with the phenotypic changes in hepatic gene expression known as the acute phase response.en_US
dc.descriptionThere is evidence that the hepatic APR serves a "priming" function for hepatocellular proliferation. As P450 depression is a feature of both the acute phase response and hepatic regeneration, it was of interest to determine if this depression occurs by a common mechanism. A protein deficiency (PD) model of hepatic regeneration has been shown to produce a G0 to G1 transition in hepatocytes (Mead et al., 1990) and was used to assess this change in cell cycle status in relation to hepatic P450 levels. The advantage of this model for this work is its absence of superimposed tissue damage and inflammation. Protein deficiency resulted in depression of total hepatic and renal P450 and elevation of pulmonary P450. Hepatic P450-related catalysis was depressed in an isoform-specific manner, with significant depression of EROD but not constitutive N-demethylase or PNPH activities. Fasting and control-fed rats exhibited distinct profiles of total P450 and catalytic activity compared to PD animals. Microsomal heme and P4502C11 exhibited depression in both PD and fasting rats.en_US
dc.descriptionSystemic inflammation inhibits P450 induction in an isoform-specific manner. If inflammation serves to prime the hepatocyte for proliferation, therefore leading to P450 depression by a mechanism common with that seen in regeneration, it would be expected that the induction of P450 isoforms would be attenuated in a similar pattern for both inflammation and regeneration (protein deficiency). It was found that the transcriptional induction of P4504A1 by clofibrate was inhibited by Poly IC (PIC) treatment but not PD, the translational induction of P4502E1 by pyridine was attenuated by PIC but not PD, while the protein stabilising effect of acetone on P4502E1 produced significant induction in PD rats but not PIC-treated animals. These findings indicate that P450 modulation by inflammation and regeneration occurs by distinct mechanisms. (Abstract shortened by UMI.)en_US
dc.descriptionThesis (Ph.D.)--Dalhousie University (Canada), 1995.en_US
dc.languageengen_US
dc.publisherDalhousie Universityen_US
dc.publisheren_US
dc.subjectHealth Sciences, Pharmacology.en_US
dc.titleRegulation of cytochrome P450 during hepatic stress responses.en_US
dc.typetexten_US
dc.contributor.degreePh.D.en_US
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