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dc.contributor.advisorJeong, Hyunyoungen_US
dc.contributor.authorNing, Miaoranen_US
dc.date.accessioned2017-10-31T17:18:10Z
dc.date.available2017-10-31T17:18:10Z
dc.date.created2017-08en_US
dc.date.issued2017-06-01en_US
dc.date.submittedAugust 2017en_US
dc.identifier.urihttp://hdl.handle.net/10027/21938
dc.description.abstractCytochrome P450 (CYP) 2D6 is a major drug-metabolizing enzyme, eliminating over 20% of clinically used drugs. CYP2D6-mediated drug metabolism exhibits large inter-individual variability. Genetic polymorphisms of CYP2D6 are known to contribute to the variability, especially in CYP2D6 poor metabolizer (PM) phenotype. However, PMs only account for 5-10% of the population, and the association between CYP2D6 genotypes and phenotypes is weak in non-PM population. Identities of factors governing CYP2D6 expression and/or activities in the majority of population remain unclear. Hereby, in 115 healthy human liver tissues, we examined multiple potential determinants of CYP2D6 activity levels including genetic polymorphisms in CYP2D6 and transcriptional regulators of CYP2D6 as well as the amounts of bile acids and retinoic acid. Our results showed that CYP2D6 activity score (a semi-quantitative collective representation of CYP2D6 genotypes) is a poor predictor of CYP2D6 activity while 59% of the variability in CYP2D6 activity is explained by CYP2D6 protein levels. CYP2D6 protein and mRNA levels were correlated with r2 of 0.11, likely reflecting the dynamics of transcriptional gene regulation. mRNA expression levels of previously known transcriptional regulators of CYP2D6 did not correlate with CYP2D6 expression or activity. Results from a series of adjusted analysis and multivariate regression showed that CYP8B1 expression (that share the same transcriptional regulatory pathway as CYP2D6) was the best predictor of CYP2D6 mRNA levels. We also examined whether physiological changes, specifically obesity and pregnancy, affect CYP2D6 or mouse endogenous CYP2D expression. Our results suggest that obesity had minimum effect on CYP2D6-mediated drug metabolism in CYP2D6 humanized mouse model. During mouse pregnancy, Cyp2d40 expression was enhanced through enhanced transactivation by HNF4α. Together, our data indicate that CYP2D6 genotypes only partially explain the variability in CYP2D6 activity in general. CYP2D6 activity level in the liver is governed predominantly by its protein amount highlighting the importance of factors involved in the regulation of CYP2D6 expression in explaining the inter-individual variability of CYP2D6-mediated drug metabolism.en_US
dc.format.mimetypeapplication/pdfen_US
dc.subjectCYP2D6en_US
dc.subjectdrug metabolismen_US
dc.subjectinter-individual variabilityen_US
dc.subjectpharmacogenomicsen_US
dc.subjectgene regulationen_US
dc.subjectobesityen_US
dc.subjectpregnancyen_US
dc.subjectCyp2d40en_US
dc.subjecten_US
dc.titleMolecular Basis of Inter-Individual Variability in Cytochrome P450 2D6-Mediated Drug Metabolismen_US
dc.typeThesisen_US
thesis.degree.departmentBiopharmaceutical Sciencesen_US
thesis.degree.grantorUniversity of Illinois at Chicagoen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhD, Doctor of Philosophyen_US
dc.contributor.committeeMemberWang, Zaijieen_US
dc.contributor.committeeMemberBarbolina, Mariaen_US
dc.contributor.committeeMemberZhang, Weien_US
dc.contributor.committeeMemberDuarte, Julioen_US
dc.type.materialtexten_US
dc.contributor.chairJeong, Hyunyoungen_US


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