Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8994325 | Journal of Pharmaceutical Sciences | 2005 | 14 Pages |
Abstract
Although much is known concerning the effects of inflammation and oxidative stress on the cytochrome P450 1A1 (CYP1A1), little is known about the modulation of other aryl hydrocarbon receptor (AHR)âregulated genes such as glutathioneâSâtransferase Ya (GST Ya) and NAD(P)H:quinone oxidoreductase (QOR) by inflammation. In the present study, the effect of tumor necrosis factor (TNF)âα and lipopolysaccharides (LPS) on the constitutive and inducible expression of the AHRâregulated genes cyp1a1, GST Ya, and QOR was determined in murine hepatoma Hepa 1c1c7 (WT), AHRâdeficient (C12), and AHR nuclear translocator protein (ARNT)âdeficient (C4) cells. We found that both TNFâα and LPS strongly repressed the constitutive expression and the βânaphthoflavoneâmediated induction of cyp1a1, GST Ya, and QOR in WT but not in C12 and C4 cells. The induction of GST Ya and QOR activities and mRNA levels by phenolic antioxidant, tertâbutylhydroquinone, through the antioxidant response element was not significantly affected by TNFâα or LPS. In addition, a significant increase in reactive oxygen species was observed in WT, C12, and C4 cells treated with TNFâα or LPS which was completely prevented by tertâbutylhydroquinone. These results show that the downâregulation of AHRâregulated genes by TNFâα and LPS is dependent on the presence of both heterodimeric transcription factors, AHR and ARNT. Furthermore, reactive oxygen species may be involved in the downâregulation of AHRâregulated genes. © 2004 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 94:493-506, 2005
Keywords
Related Topics
Health Sciences
Pharmacology, Toxicology and Pharmaceutical Science
Drug Discovery
Authors
Negar Gharavi, Ayman O.S. ElâKadi,