Joiakim Aby, Mathieu Patricia A, Palermo Christine, Gasiewicz Thomas A, Reiners John J
Institute of Environmental Health Sciences, Wayne State University, 2727 Second Ave., Rm. 4000, Detroit, MI 48201, USA.
Drug Metab Dispos. 2003 Nov;31(11):1279-82. doi: 10.1124/dmd.31.11.1279.
Exposure of the immortalized human breast epithelial cell line MCF10A to the Jun N-terminal kinase (JNK) inhibitor anthra[1,9-cd]pyrazol-6(2H)-one (SP600125) suppressed, in a concentration-dependent manner (IC50 is approximately 2 microM), the induction of CYP1A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Cotreatment with SP600125 also suppressed the accumulation of TCDD-induced nuclear aryl hydrocarbon receptor (AhR)-DNA complexes, as assessed by electrophoretic mobility shift assays. Concentrations of SP600125 < or = 50 microM did not transform the AhR into a DNA-binding species when added to rat liver cytosol. However, addition of SP600125 to cytosol just before TCDD addition completely suppressed AhR transformation and DNA binding (IC50 approximately 7 microM). Sucrose gradient analyses using rat liver and murine hepatoma 1c1c7 extracts demonstrated that SP600125 competed with TCDD for binding to the AhR. These results suggest that SP600125 is an AhR ligand and functions as an AhR antagonist at concentrations used to pharmacologically inhibit JNK.
永生化人乳腺上皮细胞系MCF10A暴露于Jun氨基末端激酶（JNK）抑制剂蒽[1,9-cd]吡唑-6(2H)-酮（SP600125）后，2,3,7,8-四氯二苯并-对-二恶英（TCDD）诱导的CYP1A1呈浓度依赖性抑制（IC50约为2 microM）。通过电泳迁移率变动分析评估，与SP600125共同处理也抑制了TCDD诱导的核芳烃受体（AhR）-DNA复合物的积累。当向大鼠肝脏胞质溶胶中添加浓度≤50 microM的SP600125时，不会将AhR转化为DNA结合形式。然而，在添加TCDD之前立即向胞质溶胶中添加SP600125可完全抑制AhR转化和DNA结合（IC50约为7 microM）。使用大鼠肝脏和小鼠肝癌1c1c7提取物进行的蔗糖梯度分析表明，SP600125与TCDD竞争与AhR的结合。这些结果表明，SP600125是一种AhR配体，在用于药理学抑制JNK的浓度下作为AhR拮抗剂发挥作用。
