Abstract

An underlying principle that governs drug-metabolizing enzymes is their broad structural diversity with a loose link to specificity. Numerous regulatory proteins dictate induction of the enzymes. Some of these proteins also exhibit structural diversity and functional promiscuity, which may also be a reflection of protein modifications and protein-protein interactions. Our basic research aims are to understand the underlying structural basis governing the functions of metabolic enzymes and the proteins that regulate expression of the enzymes. We have chosen to investigate molecular and cellular mechanisms of phenobarbital (PB) induction. PB represents a group of myriad xenobiotics that induce drug-metabolizing enzymes.A signature of PB induction is its pleiotropicity altering the expression of a large number of hepatic genes.Some of those alterations are coordinated to achieve a physiological and/or pharmacological end-point. PB also acts as tumor promoter, causing hepatocellular carcinomas in rodents.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES080040-19
Application #
7007473
Study Section
(LRDT)
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2004
Total Cost
Indirect Cost

  Institution

Name
U.S. National Inst of Environ Hlth Scis
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
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
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
Jackson, Jonathan P; Ferguson, Stephen S; Negishi, Masahiko et al. (2006) Phenytoin induction of the cyp2c37 gene is mediated by the constitutive androstane receptor. Drug Metab Dispos 34:2003-10
Tien, E S; Negishi, M (2006) Nuclear receptors CAR and PXR in the regulation of hepatic metabolism. Xenobiotica 36:1152-63

Showing the most recent 10 out of 64 publications