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dc.contributor.advisorJeong, Hyunyoungen_US
dc.contributor.authorChoi, Su-Youngen_US
dc.date.accessioned2012-12-10T19:45:05Z
dc.date.available2014-06-11T09:30:18Z
dc.date.created2012-08en_US
dc.date.issued2012-12-10
dc.date.submitted2012-08en_US
dc.identifier.urihttp://hdl.handle.net/10027/9282
dc.description.abstractPregnancy alters hepatic drug metabolism in a cytochrome P450 (CYP) isoform-specific manner, and rising concentrations of female hormones are potentially responsible for the changes. The objective of this study is to determine the effects of estradiol (E2) and progesterone (PRG) on the expression and activities of hepatic CYPs. In chapter 2, human hepatocytes were treated with E2, PRG, their combination, or known CYP inducers and the mRNA expression and activity levels of CYP were determined. The roles of orphan nuclear receptors in hormone-mediated CYP regulation were also determined by promoter activity assays. The results show that E2 enhances CYP2A6, CYP2B6, and CYP3A4 expression whereas PRG enhances CYP2A6, CYP2B6, CYP2C8, CYP3A4, and CYP3A5 expression. E2 also increased the activities of CYP2C9 and CYP2E1 without affecting the mRNA levels. A combination of estrogens and PRG exhibited an additive effect on CYP3A4 expression, but not on CYP2A6 and CYP2B6 expression. The promoter assays showed that E2 is a constitutive androstane receptor activator, and PRG is a pregnane X receptor activator. When these results were compared with the clinical observations, increased activities of CYP2A6, CYP2C9 and CYP3A4/5 during pregnancy can be, at least in part, attributable to increased female hormone levels. In Chapter 3, we characterized effects of E2 on the expression of rat hepatic CYPs in vivo. Female Sprague-Dawley rats were treated with estradiol benzoate or known CYP inducers, and the expression and activities of CYPs and their modulators were determined. The results showed that E2 enhanced the expression of CYP1A2, CYP2C6, CYP2C7, CYP2C12, and CYP3A9 while the expression of CYP3A1, PXR, CAR, and POR was downregulated. The directional changes observed in female rats are mostly different from those clinically observed during human pregnancy. In chapter 4, we evaluated DMSO-treated Huh 7 cells as an in vitro model system for drug metabolism studies. The results showed that 2% DMSO treatment dramatically induced the mRNA expression levels and activities of most DMEs in Huh7 cells. However, compared to human hepatocytes, the overall expression and activities of DMEs were still low, limiting the utility of DMSO-treated Huh7 cells as a substitution for hepatocytes.en_US
dc.language.isoenen_US
dc.rightsen_US
dc.rightsCopyright 2012 Su-Young Choien_US
dc.subjectCytochrome P450en_US
dc.subjectpregnancyen_US
dc.subjectestradiolen_US
dc.subjectprogesteroneen_US
dc.subjectprimary human hepatocytesen_US
dc.subjectdrug metabolismen_US
dc.titleHormonal Regulation of Hepatic CYP Expression: Implications in Altered Drug Metabolism during Pregnancyen_US
thesis.degree.departmentPharmacognosyen_US
thesis.degree.disciplinePharmacognosyen_US
thesis.degree.grantorUniversity of Illinois at Chicagoen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhD, Doctor of Philosophyen_US
dc.type.genrethesisen_US
dc.contributor.committeeMemberBolton, Judyen_US
dc.contributor.committeeMemberBurdette, Joannaen_US
dc.contributor.committeeMemberFischer, Jamesen_US
dc.contributor.committeeMembervan Breemen, Richarden_US
dc.type.materialtexten_US


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