Abstract

of Work: Metabolism by cytochromes P450 is a defense system against environmental toxicants and carcinogens. Consequently, the metabolic capability affects human susceptability to xenochemical exposure. To encounter virtually unlimited numbers of structurally diverse xenochemicals, P450 genes are capable of being induced in response to the exposures. Thus, finding the induction mechanism is critical for our ability to predict the susceptibility to xenochemicals. Using mouse primary hepatocytes, we have defined a 51-bp DNA found in the human CYP2B gene as the phenobarbital-responsive enhancer module or PBREM. We have also identified the nuclear orphan receptor CAR as a phenobarbital-responsive transcription factor that activates PBREM and induces the CYP2B gene. CAR is a cytosolic receptor in non-induced livers and translocates to nucleus following treatment by phenobarbital. The CAR nuclear translocation is an initial regulatory step in induction by phenobarbital of the CYP2B gene. CAR and PBREM are conserved in mouse, rat and human and can respond to not only phenobarbital but also numerous phenobarbital-type inducers, indicating their functional versatility. - Cytochrome P450, Gene regulation, Nuclear receptor, Drug metabolism, Induction, Phenobarbital

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES080040-14
Application #
6290069
Study Section
Special Emphasis Panel (LRDT)
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
National Institute of Environmental Health Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Konno, Yoshihiro; Kodama, Susumu; Moore, Rick et al. (2009) Nuclear xenobiotic receptor pregnane X receptor locks corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) onto the CYP24A1 promoter to attenuate vitamin D3 activation. Mol Pharmacol 75:265-71
Adair, Jennifer E; Stober, Vandy; Sobhany, Mack et al. (2009) Inter-alpha-trypsin inhibitor promotes bronchial epithelial repair after injury through vitronectin binding. J Biol Chem 284:16922-30
Timsit, Yoav E; Negishi, Masahiko (2007) CAR and PXR: the xenobiotic-sensing receptors. Steroids 72:231-46
Nakamura, Kouichi; Moore, Rick; Negishi, Masahiko et al. (2007) Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver. J Biol Chem 282:9768-76
Yamazaki, Yuichi; Kakizaki, Satoru; Horiguchi, Norio et al. (2007) The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis. Gut 56:565-74
Phillips, Jennifer M; Yamamoto, Yukio; Negishi, Masahiko et al. (2007) Orphan nuclear receptor constitutive active/androstane receptor-mediated alterations in DNA methylation during phenobarbital promotion of liver tumorigenesis. Toxicol Sci 96:72-82
Tien, Eric S; Matsui, Kenji; Moore, Rick et al. (2007) The nuclear receptor constitutively active/androstane receptor regulates type 1 deiodinase and thyroid hormone activity in the regenerating mouse liver. J Pharmacol Exp Ther 320:307-13
Koike, Chika; Moore, Rick; Negishi, Masahiko (2007) Extracellular signal-regulated kinase is an endogenous signal retaining the nuclear constitutive active/androstane receptor (CAR) in the cytoplasm of mouse primary hepatocytes. Mol Pharmacol 71:1217-21
Sobhany, Mack; Negishi, Masahiko (2006) Characterization of specific donor binding to alpha1,4-N-acetylhexosaminyltransferase EXTL2 using isothermal titration calorimetry. Methods Enzymol 416:3-12
Inoue, Kaoru; Borchers, Christoph H; Negishi, Masahiko (2006) Cohesin protein SMC1 represses the nuclear receptor CAR-mediated synergistic activation of a human P450 gene by xenobiotics. Biochem J 398:125-33

Showing the most recent 10 out of 64 publications