Down‐regulation of aryl hydrocarbon receptor-regulated genes by tumor necrosis factor‐α and lipopolysaccharide in murine hepatoma hepa 1c1c7 cells

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)‐regulated genes such as glutathione‐S‐transferase Ya (GST Ya) and NAD(P)H:quinone oxidoreductase (QOR) by inflammation. In the present study, the effect of tumor necrosis factor (TNF)‐α and lipopolysaccharides (LPS) on the constitutive and inducible expression of the AHR‐regulated genes cyp1a1, GST Ya, and QOR was determined in murine hepatoma Hepa 1c1c7 (WT), AHR‐deficient (C12), and AHR nuclear translocator protein (ARNT)‐deficient (C4) cells. We found that both TNF‐α and LPS strongly repressed the constitutive expression and the β‐naphthoflavone‐mediated 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, tert‐butylhydroquinone, through the antioxidant response element was not significantly affected by TNF‐α or LPS. In addition, a significant increase in reactive oxygen species was observed in WT, C12, and C4 cells treated with TNF‐α or LPS which was completely prevented by tert‐butylhydroquinone. These results show that the down‐regulation of AHR‐regulated genes by TNF‐α and LPS is dependent on the presence of both heterodimeric transcription factors, AHR and ARNT. Furthermore, reactive oxygen species may be involved in the down‐regulation of AHR‐regulated genes. © 2004 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:493-506, 2005