Suppression by p38 MAP kinase inhibitors (pyridinyl imidazole compounds) of Ah receptor target gene activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and the possible mechanism
Suppression by p38 MAP kinase inhibitors (pyridinyl imidazole compounds) of Ah receptor target gene activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and the possible mechanism
复制标题
DOI：
10.1074/jbc.m305880200
复制
发表时间：
2004-01-30
影响因子：
4.8
通讯作者：
Kikuchi, H
中科院分区：
文献类型：
--
作者：
Shibazaki, M;Takeuchi, T;Kikuchi, H
细胞色素P-450 1A1(CYP1A1)是由芳香族化合物如2，3，7，8-四氯二苯并-对二恶英(TCDD)通过激活芳香烃受体(AhR)诱导的。我们发现p38 MAPK抑制剂(SB203580和SB202190，各40微米；吡啶基咪唑类化合物)能抑制TCDD(2 NM)对小鼠肝癌HEPA-1细胞和人肝癌细胞HepG2细胞的CYP1A1-mRNA的诱导，也能抑制TCDD(2 NM)对人乳腺癌MCF7细胞的CYP1B1-mRNA的诱导。不抑制p38 MAP激酶的类似物SB202474也能抑制TCDD诱导的细胞色素P1A1-mRNA表达。此外，在HEPA-1细胞中过表达p38MAPK的显性负性基因并不能抑制TCDD对Cyp1a1报告基因的诱导。因此，吡啶基咪唑类化合物对Cyp1a1转录的抑制并不是因为它们抑制了p38 MAP激酶的活性。由于SB203580不能抑制TCDD在体外对AhR的转化，因此该化合物不是一个简单的AhR拮抗剂。SB203580降低了TCDD诱导的Cyp1a1基因启动子区域的组蛋白乙酰化水平，尤其是在TATA盒序列附近。这一结果表明，吡啶基咪唑类化合物可能抑制了某些具有组蛋白乙酰转移酶活性的共激活剂的招募，组蛋白乙酰转移酶是CYP1A1-mRNA转录所必需的。
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 muM 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.