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.
|Yang, Hui; Garzel, Brandy; Heyward, Scott et al. (2014) Metformin represses drug-induced expression of CYP2B6 by modulating the constitutive androstane receptor signaling. Mol Pharmacol 85:249-60|
|Sueyoshi, Tatsuya; Li, Linhao; Wang, Hongbing et al. (2014) Flame retardant BDE-47 effectively activates nuclear receptor CAR in human primary hepatocytes. Toxicol Sci 137:292-302|
|Garzel, Brandy; Yang, Hui; Zhang, Lei et al. (2014) The role of bile salt export pump gene repression in drug-induced cholestatic liver toxicity. Drug Metab Dispos 42:318-22|
|Yang, Hui; Wang, Hongbing (2014) Signaling control of the constitutive androstane receptor (CAR). Protein Cell 5:113-23|
|Lynch, Caitlin; Pan, Yongmei; Li, Linhao et al. (2014) Activation of the constitutive androstane receptor inhibits gluconeogenesis without affecting lipogenesis or fatty acid synthesis in human hepatocytes. Toxicol Appl Pharmacol 279:33-42|
|Lynch, Caitlin; Pan, Yongmei; Li, Linhao et al. (2013) Identification of novel activators of constitutive androstane receptor from FDA-approved drugs by integrated computational and biological approaches. Pharm Res 30:489-501|
|Wang, Duan; Li, Linhao; Yang, Hui et al. (2013) The constitutive androstane receptor is a novel therapeutic target facilitating cyclophosphamide-based treatment of hematopoietic malignancies. Blood 121:329-38|
|Ou, Zhimin; Shi, Xiongjie; Gilroy, Richard K et al. (2013) Regulation of the human hydroxysteroid sulfotransferase (SULT2A1) by ROR? and ROR? and its potential relevance to human liver diseases. Mol Endocrinol 27:106-15|
|Hassan, Hazem E; Myers, Alan L; Lee, Insong J et al. (2013) Induction of xenobiotic receptors, transporters, and drug metabolizing enzymes by oxycodone. Drug Metab Dispos 41:1060-9|
|Li, Linhao; Sinz, Michael W; Zimmermann, Kurt et al. (2012) An insulin-like growth factor 1 receptor inhibitor induces CYP3A4 expression through a pregnane X receptor-independent, noncanonical constitutive androstane receptor-related mechanism. J Pharmacol Exp Ther 340:688-97|
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