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dc.contributor.advisorTian, Yananen_US
dc.creatorGu, Xinshengen_US
dc.date.accessioned2010-01-14T23:57:48Zen_US
dc.date.accessioned2010-01-16T02:00:26Z
dc.date.available2010-01-14T23:57:48Zen_US
dc.date.available2010-01-16T02:00:26Z
dc.date.created2007-08en_US
dc.date.issued2009-05-15en_US
dc.identifier.urihttp://hdl.handle.net/1969.1/ETD-TAMU-1630
dc.description.abstractCytochrome P450 3A4 (CYP3A4) is a key enzyme responsible for the metabolism of drugs and endogenous compounds in human liver and intestine. CYP3A4 gene expression is mainly regulated by Pregnane X receptor (PXR) which is a ligand-dependent nuclear receptor. It is a long-standing observation that inflammatory responses and infections decrease drug metabolism capacity in human and experimental animals. In this study, I reported that NF-κB activation by LPS and TNF-α plays a pivotal role in the suppression of CYP3A4 through interactions of NF-κB with PXR/RXR complex. Inhibition of NF-κB by NF-κB specific suppressor SRIκBα reversed the suppressive effects of LPS and TNF-α. Furthermore, I showed that NF-κB p65 disrupted the association of PXR/RXRα complex with DNA sequences as determined by EMSA and chromatin immunoprecipitation assays. NF-κB p65 directly interacted with DNA binding domain of RXRα and DNA binding domain, hinge domain and ligand-binding domain of PXR and may prevent its binding to the consensus DNA sequences, thus inhibiting the transactivation by PXR/RXRα complex. This mechanism of suppression by NF-κB activation may be extended to other nuclear receptor-regulated systems where RXRα is a dimerization partner. Many genes regulated by PXR and AhR are important for phase I, II and III drug metabolism. In this study I reported a crosstalk between PXR and AhR pathways. AhR physically and functionally interacted with PXR and enhanced the PXR transcriptional activity, and the interaction repressed the AhR transcriptional activity. AhR also physically interacted with RXRα. The synergistic induction of Gsta1 in the liver of mice by PCN and TCDD might assume a different mechanism. The results suggested the metabolism kinetics of mixture drugs was different from and more complicated than that of single compound. Using a HepG2 cell-based PXR-driven CYP3A4-Luciferase assay, I reported that E/F domain of PXR was responsible for ligand-dependant activation. A/B domain was necessary for co-activating the ligand-dependent activation and D domain was suppressive. High doses of Valerian Root extraction were PXR-dependent CYP3A4 inducers. Green tea polyphenols, aflatoxin B1, CuSO4 and MnCl2 enhanced the PXR transcription activity activated by rifampicin. The results suggested PXR-mediated drug metabolism kinetics altered on xenobiotic exposure.en_US
dc.format.mediumelectronicen_US
dc.format.mimetypeapplication/pdfen_US
dc.language.isoen_USen_US
dc.subjectcytochrome P450 3A4en_US
dc.subjectPregnane X Receptoren_US
dc.titleRegulation of cytochrome P450 3A4 gene expression through modulating pregnane X receptor transcriptional activity by NF-ꢬ aryl hydrocarbon receptor and xenobioticsen_US
dc.typeBooken
dc.typeThesisen
thesis.degree.departmentVeterinary Physiology and Pharmacologyen_US
thesis.degree.disciplineToxicologyen_US
thesis.degree.grantorTexas A&M Universityen_US
thesis.degree.nameDoctor of Philosophyen_US
thesis.degree.levelDoctoralen_US
dc.contributor.committeeMemberDonnelly, Kirby C.en_US
dc.contributor.committeeMemberPorter, Weston W.en_US
dc.contributor.committeeMemberSafe, Stephen H.en_US
dc.type.genreElectronic Dissertationen_US
dc.type.materialtexten_US
dc.format.digitalOriginborn digitalen_US


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