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We have previously shown that the p38 MAPK inhibitor SB203580 (SB) significantly induced Cyp1a1 gene expression at the mRNA and activity levels, whereas it dramatically inhibited the induction of Cyp1a1 by TCDD in murine hepatoma Hepa 1c1c7 cells. However, the molecular mechanisms involved were not investigated yet. Therefore, the current study aims to examine the capacity of SB to induce the constitutive CYP1A1 gene expression in Hepa 1c1c7 and HepG2 cells and to explore the mechanisms involved. Our results showed that SB induced the Cyp1a1 mRNA, protein, and activity levels in a concentration-dependent manner in Hepa 1c1c7 cells. The increase in Cyp1a1 mRNA by SB was completely blocked by the transcriptional inhibitor, actinomycin D, implying that SB increased de novo RNA synthesis. In addition, the lack of Cyp1a1 induction by SB in mutant aryl hydrocarbon receptor (AhR)-deficient C12 cells and with cotreatment with the AhR antagonist, α-naphthoflavone, clearly suggests an AhR-dependent induction. This was further supported by the ability of SB to induce Cyp1a1 independent from its effect on MAPKs, and to bind to and activate AhR transformation and its subsequent binding to the xenobiotic responsive element (XRE). This is the first demonstration that the p38 MAPK inhibitor, SB can directly bind to and activate AhR-induced Cyp1a1 gene expression in an AhR-dependent manner and represents a novel mechanism by which SB induces this enzyme.

chemical research in toxicology

The p38 MAPK Inhibitor SB203580 Induces Cytochrome P450 1A1 Gene Expression in Murine and Human Hepatoma Cell Lines through Ligand-Dependent Aryl Hydrocarbon Receptor Activation