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Molecular Basis of Inter-Individual Variability in Cytochrome P450 2D6-Mediated Drug Metabolism

1:00 pm - 2:00 pm, May 24, 2017

Dissertation Defense:

“Molecular Basis of Inter-Individual Variability in Cytochrome P450 2D6-Mediated Drug Metabolism”

Miaoran Ning
Ph.D. Candidate

Advisor:  Dr. Hyun-Young Jeong
Department of Biopharmaceutical Sciences
UIC

May 24, 2017 (Wednesday)
1:00 PM - 2:00 PM
Room B36 COP
Room E211 COMRP ROCKFORD
833 S Wood Street
Chicago, IL

Abstract: Cytochrome 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. 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.

Event Details

Location: College of Pharmacy
Room: B36/Rockford COMRP E211
Address:
833 S Wood St
Chicago, IL

Sponsor: Department of Biopharmaceutical Sciences

Contact Name: Celina Tejada
Contact Email: tejada@uic.edu
Contact Phone: 312-996-0888

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Date Posted: Thu, May 18
Date Updated: Thu, May 18

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