Unintentional drug over- or under-dosing is an enormous clinical problem. The large interindividual variability in CYP2D6-mediated drug metabolism is a critical contributor to this problem, as it is responsible for the unpredictable occurrence of adverse drug outcomes in response to a given dose of a CYP2D6 substrate. It is known that genetic polymorphisms of CYP2D6 partially explain the variability, especially for the poor metabolizer phenotype; however, they fail to explain the majority of variability in the remaining population (~90%). Accumulating evidence strongly indicates that differential regulation of CYP2D6 at the transcriptional level plays a key role in determining CYP2D6-mediated drug metabolism. In healthy human liver tissues, mRNA levels of CYP2D6 were highly correlated with the enzyme's activity. The level of correlation was similar to that for CYP3A4, a gene whose expression is controlled mainly at the transcriptional level. Despite this evidence, factors governing CYP2D6 transcription are poorly understood. Thus, there is a substantial gap in our understanding of the interindividual variability that lead to adverse drug reactions or drug inefficacy. The long-term goal of our research is to develop approaches to better predict the highly variable CYP2D6 activity in individuals. Our hypothesis is that genetic and environmental factors regulate the expression/activity of a specific transcription factor, small heterodimer partner (SHP), which in turn alters CYP2D6 expression. We further hypothesize that this is in part responsible for the interindividual variability in CYP2D6 expression. Our hypothesis is based on our recent finding in CYP2D6-humanized transgenic (Tg-CYP2D6) mice that SHP represses CYP2D6 expression. Moreover, compounds enhancing SHP expression repress hepatic CYP2D6 expression, and SHP and CYP2D6 expression is negatively correlated in human liver tissues. These data strongly suggest that SHP plays a key role in regulating CYP2D6 expression and that differential expression of SHP leads to CYP2D6 variability. To test our hypothesis, we propose the following specific aims: (1) Determine the extent to which SHP modulators cause alterations of CYP2D6 expression in Tg-CYP2D6 mice, and (2) Identify SHP modulators that explain CYP2D6 variability in human liver tissues. Current efforts to predict CYP2D6 activity rely exclusively on the CYP2D6 genotypes and fail to explain CYP2D6 variability in the majority of the population. The proposed work is expected to reveal previously unknown contributors to CYP2D6 variability (namely extrinsic and genetic factors controlling the expression and/or activity of SHP) and, thus, improve the ability to predict CYP2D6 activity. We believe this will ultimately lead to the development of strategies to minimize the risk of dangerous drug over- and under-dosing with CYP2D6 substrates.

Public Health Relevance

Unintentional drug over- or under-dosing is an enormous clinical problem. Person-to-person variability in the rate of drug elimination is a critical contributor to the problem. We propose to identify factors underlying the variability in hepatic drug metabolism. The results obtained from this study should lay a foundation for developing approaches to adjust therapy and avoid dangerous drug over- and under-dosing.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM112746-01A1
Application #
8960222
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2015-07-01
Project End
2019-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Morgan, Edward T; Dempsey, Joseph L; Mimche, Sylvie M et al. (2018) Physiological Regulation of Drug Metabolism and Transport: Pregnancy, Microbiome, Inflammation, Infection, and Fasting. Drug Metab Dispos 46:503-513
Ning, Miaoran; Duarte, Julio D; Rubin, Leah H et al. (2018) CYP2D6 Protein Level Is the Major Contributor to Interindividual Variability in CYP2D6-Mediated Drug Metabolism in Healthy Human Liver Tissue. Clin Pharmacol Ther 104:974-982
Kent, Rebecca; Jeong, Hyunyoung (2017) Effects of Fenofibrate on the Expression of Small Heterodimer Partner (SHP) and Cytochrome P450 (CYP) 2D6. Drug Metab Lett 11:68-72
Ning, Miaoran; Jeong, Hyunyoung (2017) High-Fat Diet Feeding Alters Expression of Hepatic Drug-Metabolizing Enzymes in Mice. Drug Metab Dispos 45:707-711
Pan, Xian; Ning, Miaoran; Jeong, Hyunyoung (2017) Transcriptional Regulation of CYP2D6 Expression. Drug Metab Dispos 45:42-48
Pan, Xian; Kent, Rebecca; Won, Kyoung-Jae et al. (2017) Cholic Acid Feeding Leads to Increased CYP2D6 Expression in CYP2D6-Humanized Mice. Drug Metab Dispos 45:346-352
Cho, Sung-Joon; Ning, Miaoran; Zhang, Yanyan et al. (2016) 17?-Estradiol up-regulates UDP-glucuronosyltransferase 1A9 expression via estrogen receptor ?. Acta Pharm Sin B 6:504-509
Tracy, Timothy S; Chaudhry, Amarjit S; Prasad, Bhagwat et al. (2016) Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism. Drug Metab Dispos 44:343-51
Pan, Xian; Jeong, Hyunyoung (2015) Estrogen-Induced Cholestasis Leads to Repressed CYP2D6 Expression in CYP2D6-Humanized Mice. Mol Pharmacol 88:106-12