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.
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.
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