Suppression of CYP1A1 transcription by H2O2 is mediated by xenobiotic-response element.
Suppression of CYP1A1 transcription by H2O2 is mediated by xenobiotic-response element.
复制标题
H2O2 对 CYP1A1 转录的抑制是由异生素反应元件介导的。
DOI：
10.1006/abbi.1998.0770
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Pasco,DS
中科院分区：
文献类型：
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作者：
Xu,C;Pasco,DS
我们之前已经证明h2o2在分离的大鼠肝细胞中下调cyp1a1和cyp1a2的转录(C. W. Barker等，1994，J。医学杂志。Chem.269, 3985 - 3990)。在本研究中，由3.1 kb ratcyp1a1上游调控序列驱动的氯霉素乙酰转移酶（CAT）表达在H2O2处理的Hepa-1细胞中被抑制了56%。同样，h2o2抑制含有两个异种反应元件（xre1）或XRE2拷贝的载体的CAT表达。在未使用诱导剂β-萘黄酮处理的细胞中，h2o2不抑制CAT的基础表达。电泳迁移率转移实验表明h2o2对xre依赖性转录的抑制不是由于核芳烃（Ah）受体DNA结合活性的改变。几种类型的实验表明，通过各种方式调节XRE增强子的强度可以改变h2o2依赖性的CAT表达抑制。增加Ah受体的反激活电位（增加XRE拷贝数或缩短XREs与最小cyp1a1启动子之间的距离）的条件会减弱H2O2的作用，而降低XRE介导的反激活电位（减少XRE拷贝数、增加XRE与启动子之间的距离或通过降低诱导剂浓度减少结合Ah受体的数量）的条件会增强H2O2的抑制作用。
We have previously demonstrated that H2O2downregulatesCYP1A1andCYP1A2transcription in isolated rat hepatocytes (C. W. Barker,et al., 1994,J. Biol. Chem.269, 3985–3990). In the present study, induction of chloramphenicol acetyltransferase (CAT) expression driven by 3.1 kb of ratCYP1A1upstream regulatory sequences was suppressed by 56% in Hepa-1 cells treated with H2O2. Similarly, H2O2inhibited CAT expression from vectors containing two copies of either xenobiotic-response element (XRE) 1 or XRE2. H2O2did not inhibit basal CAT expression in cells that were not treated with the inducer β-napthoflavone. Electrophoretic mobility shift assays demonstrated that the suppression of XRE-dependent transcription by H2O2was not due to changes in nuclear aryl hydrocarbon (Ah) receptor DNA binding activity. Several types of experiments indicated that modulation of XRE enhancer strength by various means could modify H2O2-dependent suppression of CAT expression. Conditions that increased the transactivation potential of the Ah receptor (increase in XRE copy number or shortening of the distance between XREs and the minimalCYP1A1promoter) attenuated the action of H2O2, while conditions that reduced XRE-mediated transactivation potential (decrease in XRE copy number, increase of the distance between the XRE and the promoter, or reduction of the number of bound Ah receptors by lowering the concentration of inducer) potentiated the inhibitory action of H2O2.