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dc.contributor.advisorJeong, Hyunyoungen_US
dc.contributor.authorZhang, Shuen_US
dc.date.accessioned2017-03-07T22:24:48Z
dc.date.available2017-03-07T22:24:48Z
dc.date.created2016-12en_US
dc.date.issued2016-10-10en_US
dc.date.submittedDecember 2016en_US
dc.identifier.urihttp://hdl.handle.net/10027/21630
dc.description.abstractSmall heterodimer partner (SHP) is a transcriptional corepressor of a number of ligand regulated nuclear receptors (NR) and orphan receptors, and represses their target genes expression. Studying transcriptional regulation mechanism of important DMEs can help better understand and predict of the elimination of drugs, and effectively achieve personalized medicine. Farnesoid X receptor (FXR) functions as a regulator of bile acid and lipid homeostasis, and is recognized as a promising therapeutic target for metabolic diseases. SHP is the target gene of several signaling pathways, and various inducers significantly increase its expression. In Chapter 1, we investigated the effect of FXR activation on the expression of the major drug-metabolizing enzyme, CYP3A4. The results in Chapter 1 showed that in human hepatocytes, treatment of GW4064 (1 μM) for 48 hours resulted in 75% decrease in CYP3A4 mRNA expression and 25% decrease in CYP3A4 activity, accompanied by ~3-fold increase in SHP mRNA expression. In HepG2 cells, SHP repressed transactivation of CYP3A4 promoter by pregnane X receptor (PXR), constitutive androstane receptor (CAR), and glucocorticoid receptor (GR). Interestingly, GW4064 did not repress expression of CYP2B6, another target gene of PXR and CAR; GW4064 was shown to enhance CYP2B6 promoter activity. In conclusion, GW4064 represses CYP3A4 expression in human hepatocytes, potentially through upregulation of SHP expression and subsequent repression of CYP3A4 promoter activity. Clinically significant drug-drug interaction involving FXR agonists and CYP3A4 substrates may occur. In Chapter 2, we characterized the effect of ATRA, another potential inducer of SHP, on CYP2D6 expression in vitro and in vivo. Results showed in both human hepatocytes and transgenic mices, CYP2D6 mRNA expression level was significantly repressed by ~70% in vitro, and by ~50% in vivo. The repressed CYP2D6 expression is accompanied by induced SHP expression which was elevated by ~3-fold in vitro and ~5-fold in vivo, respectively. The correlation between SHP and CYP2D6 was further confirmed using mice with Tg-CYP2D6 with Shp knockout compared with Tg- CYP2D6 wild-type mice. Overall, the results indicated that SHP is a key regulator in ATRA- induced CYP2D6 repression.en_US
dc.format.mimetypeapplication/pdfen_US
dc.subjectCytochrome P450, CYP3A4, CYP2D6, FXR, ATRAen_US
dc.titleTranscriptional Regulation of CYP3A4 and CYP2D6 by Small Heterodimer Partneren_US
dc.typeThesisen_US
thesis.degree.departmentBiopharmaceutical Sciencesen_US
thesis.degree.grantorUniversity of Illinois at Chicagoen_US
thesis.degree.levelMastersen_US
thesis.degree.nameMS, Master of Scienceen_US
dc.contributor.committeeMemberHong, Seungpyoen_US
dc.contributor.committeeMemberLarsen, Karlen_US
dc.type.materialtexten_US
dc.contributor.chairJeong, Hyunyoungen_US


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