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NF‐κB and AP‐1 are key signaling pathways in the modulation of NAD(P)H:Quinone oxidoreductase 1 gene by mercury, lead, and copper
Author(s) -
Korashy Hesham M.,
ElKadi Ayman O. S.
Publication year - 2008
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.20238
Subject(s) - chemistry , activator (genetics) , nad+ kinase , mapk/erk pathway , signal transduction , p38 mitogen activated protein kinases , nf κb , transcription factor , buthionine sulfoximine , oxidative stress , messenger rna , microbiology and biotechnology , glutathione , biochemistry , enzyme , biology , gene
Abstract We have previously shown that Hg 2+ , Pb 2+ , and Cu 2+ , significantly modulate the expression of NAD(P):quinone oxidoreductase 1 (Nqo1) in Hepa 1c1c7 cells through oxidative stress‐dependent mechanisms. In the current study, we examined the role of redox‐sensitive transcription factors, NF‐κB and AP‐1 signaling pathways in the modulation of Nqo1 by heavy metals. Our results show that the depletion of cellular GSH using L ‐buthionine‐(S,R)‐sulfoximine further potentiated the heavy metal‐mediated induction of Nqo1 at the mRNA and activity levels. The NF‐κB activator, PMA, significantly abolished the metal‐mediated effects on Nqo1 mRNA and activity. In parallel, the NF‐κB inhibitor, PDTC, further potentiated the Pb 2+ ‐ and Hg 2+ ‐mediated induction of Nqo1 mRNA and activity levels, respectively. Inhibition of AP‐1 upstream signaling pathway such as JNK by SP600125 significantly suppressed heavy metal‐mediated induction of Nqo1 mRNA and activity levels. In contrast, inhibition of ERK by U0126 further potentiated heavy metal‐mediated effects on Nqo1 mRNA, while only potentiated Hg 2+ ‐mediated induction of Nqo1 activity. Furthermore, p38 MAPK inhibitor, SB203580 further potentiated Pb 2+ ‐ and Cu 2+ ‐mediated effects at the mRNA levels, whereas did not alter the activity levels. These results clearly demonstrate that activation of NF‐κB negatively regulates the expression of Nqo1 by heavy metals, whereas AP‐1 signaling pathways differentially modulates the heavy metal‐mediated effects. © 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:274–283, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20238