Abstract
Cytochrome P-450 1A1 (CYP1A1) is known to be induced by aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), through activation of the aryl hydrocarbon receptor (AhR). We found that p38 MAP kinase inhibitors (SB203580 and SB202190; 40 microm each; pyridinyl imidazole compounds) suppressed CYP1A1-mRNA induction by TCDD (2 nm) in mouse hepatoma Hepa-1 cells and in human hepatoma HepG2 cells, and also suppressed CYP1B1-mRNA induction by TCDD (2 nm) in human breast adenocarcinoma MCF7 cells. An analogue compound, SB202474, which does not inhibit p38 MAP kinase, also suppressed CYP1A1-mRNA induction by TCDD. Moreover, overexpression of a dominant-negative gene for p38 MAP kinase in Hepa-1 cells did not suppress Cyp1a1 reporter gene induction by TCDD. Therefore, the suppression of Cyp1a1 transcription by pyridinyl imidazole compounds is not because of their inhibition of p38 MAP kinase activity. Because SB203580 did not inhibit in vitro AhR transformation by TCDD, this compound was not acting as a simple AhR antagonist. SB203580 decreased TCDD-induced histone acetylation levels in the region of the Cyp1a1 gene promoter, especially around the TATA box sequence. This result suggests the possibility that pyridinyl imidazole compounds suppress the recruitment of some co-activator that has the histone acetyltransferase activity necessary for CYP1A1-mRNA transcription.
Highlights
Polycyclic aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)1 and 3-methylcholanthrene, are widespread environmental pollutants with many cytotoxic and biological effects
We found that p38 MAP kinase inhibitors (SB203580 and SB202190; 40 M each; pyridinyl imidazole compounds) suppressed Cytochrome P-450 1A1 (CYP1A1)-mRNA induction by TCDD (2 nM) in mouse hepatoma Hepa-1 cells and in human hepatoma HepG2 cells, and suppressed CYP1B1-mRNA induction by TCDD (2 nM) in human breast adenocarcinoma MCF7 cells
The aryl hydrocarbon receptor (AhR) is a ligand-activated cytosolic protein that is a member of the family of the basichelix-loop-helix-Per/AhR nuclear translocator (ARNT)/Sim transcription factors, and it regulates the induction of the Cyp1a1 gene [5]
Summary
Polycyclic aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene, are widespread environmental pollutants with many cytotoxic and biological effects. Puga and co-workers [14] showed that TCDD treatment induced a transient activation of transcription factors, especially AP-1, in Hepa-1 cells, and that this activation was AhR-dependent [14] They reported that TCDD affected the expression level of various genes, including those for members of Ras/MAPK-related signaling pathways in HepG2 cells [15]. The MAP kinase pathway of p38 activates transcription factor ATF-2, and regulates the transcription of target genes by binding to its regulatory sequence, AP-1 [12] This cascade can be blocked by a series of pyridinyl imidazole compounds, exemplified by SB203580, which were originally identified by their ability to suppress the synthesis of inflammatory cytokines [16]. In the course of experiments with such chemical inhibitors, we found that CYP1A1-mRNA induction by TCDD was potently suppressed by pre-treatment of Hepa-1 cells with pyridinyl imidazole compounds
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