The importance of CYP2B6 in drug metabolism and detoxification has been firmly established through a plethora of studies in the past decade. Although it was regarded historically as a minor enzyme with insignificant roles in pharmacology and toxicology, increasing evidence demonstrated that the relative contribution of CYP2B6 to hepatic P450 content and xenobiotics metabolism is much higher than previously estimated. The dramatic individual variability in hepatic CYP2B6 expression is closely associated with the variable systemic exposure and therapeutic response to a growing list of drugs that are CYP2B6 substrates. The long-term objective of this ongoing project continues to be elucidating the molecular mechanisms governing transcriptional regulation of human hepatic CYP2B6. Results from prior funding period clearly established human (h) PXR and CAR as the major transcription factors capable of regulating CYP2B6 induction by many drugs. However, significant interindividual variations of CYP2B6 induction cannot be explained entirely by the simplified PXR/CAR-based induction model. Recently, several studies including our own data indicated that expression of CYP2B6 gene can be influenced by liver-enriched transcriptional factors (LETFs) such as hepatic nuclear factor 4? and CCAAT/enhancer-binding protein alpha. In this proposed application, we hypothesize that specific interaction between PXR/CAR and LETFs can contribute significantly to the differential induction of hepatic CYP2B6 among individuals. We plan to test this central hypothesis by the following specific aims:
Aim #1. Characterize the association between CYP2B6 induction and the expression of LETFs;
Aim #2. Determine the mechanism(s) underlying the interplay between PXR/CAR and LETFs;
and Aim #3. Define the interaction between polymorphism(s) in CYP2B6 promoter and PXR/CAR activation. The outcomes are expected to provide novel information on the regulation of CYP2B6 induction among individuals, and to bridge the knowledge gap between CYP2B6 genetic variation and nuclear receptor-mediated induction, which may coordinately contribute to the large individual variability of CYP2B6 expression and drug response.

Public Health Relevance

The proposed studies aim to provide fundamental and novel information on the regulation of CYP2B6 induction through specific interactions between PXR/CAR and liver-enriched transcription factors. The outcome from these studies is also expected to fill the knowledge gap between CYP2B6 genetic variation and nuclear receptor-mediated induction. Such information is important from both a basic pharmacological and clinical standpoint, and it will ultimately allow more accurate prediction of metabolic-associated therapeutic benefit vs. risk for drugs that are CYP2B6 substrates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061652-10
Application #
8296532
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Serrano, Jose
Project Start
2002-04-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$333,863
Indirect Cost
$116,363
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Mackowiak, Bryan; Li, Linhao; Welch, Matthew A et al. (2017) Molecular Basis of Metabolism-Mediated Conversion of PK11195 from an Antagonist to an Agonist of the Constitutive Androstane Receptor. Mol Pharmacol 92:75-87
Zuo, Rongjun; Li, Feng; Parikh, Sweta et al. (2017) Evaluation of a Novel Renewable Hepatic Cell Model for Prediction of Clinical CYP3A4 Induction Using a Correlation-Based Relative Induction Score Approach. Drug Metab Dispos 45:198-207
Li, Linhao; Li, Daochuan; Heyward, Scott et al. (2016) Transcriptional Regulation of CYP2B6 Expression by Hepatocyte Nuclear Factor 3? in Human Liver Cells. PLoS One 11:e0150587
Mackowiak, Bryan; Wang, Hongbing (2016) Mechanisms of xenobiotic receptor activation: Direct vs. indirect. Biochim Biophys Acta 1859:1130-1140
Hedrich, William D; Hassan, Hazem E; Wang, Hongbing (2016) Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B 6:413-425
Fahmi, Odette A; Shebley, Mohamad; Palamanda, Jairam et al. (2016) Evaluation of CYP2B6 Induction and Prediction of Clinical Drug-Drug Interactions: Considerations from the IQ Consortium Induction Working Group-An Industry Perspective. Drug Metab Dispos 44:1720-30
Jackson, Jonathan P; Li, Linhou; Chamberlain, Erica D et al. (2016) Contextualizing Hepatocyte Functionality of Cryopreserved HepaRG Cell Cultures. Drug Metab Dispos 44:1463-79
Lynch, Caitlin; Zhao, Jinghua; Wang, Hongbing et al. (2016) Quantitative High-Throughput Luciferase Screening in Identifying CAR Modulators. Methods Mol Biol 1473:33-42
Hedrich, William D; Xiao, Jingwei; Heyward, Scott et al. (2016) Activation of the Constitutive Androstane Receptor Increases the Therapeutic Index of CHOP in Lymphoma Treatment. Mol Cancer Ther 15:392-401
Wang, An-Jiang; Yang, Zhonghan; Grinchuk, Viktoriya et al. (2015) IL-25 or IL-17E Protects against High-Fat Diet-Induced Hepatic Steatosis in Mice Dependent upon IL-13 Activation of STAT6. J Immunol 195:4771-80

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