Repression of cytochrome P450 1A1 gene expression by oxidative stress: mechanisms and biological implications
Repression of cytochrome P450 1A1 gene expression by oxidative stress: mechanisms and biological implications
复制标题
DOI：
10.1016/s0006-2952(00)00543-8
复制
发表时间：
2001-03-01
影响因子：
5.8
通讯作者：
Morel, Y
中科院分区：
文献类型：
--
作者：
Barouki, R;Morel, Y
细胞色素 P350 1A1 (CYP1A1) 是异生素代谢酶多基因家族的成员。除了其在多环芳香族化合物解毒中的通常作用之外，这种酶的活性可能是有害的，因为它可以产生诱变代谢物和氧化应激。 CYP1A1 基因很容易被环境污染物二恶英和苯并[a]芘诱导。我们在这里讨论限制这种诱导的监管机制。几个反馈回路控制该基因的激活以及随后的潜在毒性。 CYP1A1 基因的氧化抑制似乎在这些调节中发挥着核心作用。转录因子核因子 I/CCAAT 转录因子 (NFI/CTF) 对于 CYP1A1 基因启动子的反式激活非常重要，对氧化应激特别敏感。 NFI/CTF 反式激活域内的一个关键半胱氨酸似乎是 H2O2 的目标。几种转录因子的 DNA 结合域已被描述为氧化应激的靶标。然而，这里描述的最近研究表明，应该更多地关注可能代表细胞信号传导的生物学相关氧化还原靶标的反式激活域。 (C) 2001 Elsevier Science Inc. 保留所有权利。
Cytochrome P350 1A1 (CYP1A1) is a member of a multigenic family of xenobiotic-metabolizing enzymes. Beyond its usual role in the detoxification of polycyclic aromatic compounds, the activity of this enzyme can be deleterious since it can generate mutagenic metabolites and oxidative stress. The CYP1A1 gene is highly inducible by the environmental contaminants dioxin and benzo[a]pyrene. We discuss here the regulatory mechanisms that limit this induction. Several feedback loops control the activation of this gene and the subsequent potential toxicity. The oxidative repression of the CYP1A1 gene seems to play a central role in these regulations. The transcription factor Nuclear Factor I/CCAAT Transcription Factor (NFI/CTF), which is important for the transactivation of the CYP1A1 gene promoter, is particularly sensitive to oxidative stress. A critical cysteine within the transactivating domain of NFI/CTF appears to be the target of H2O2. The DNA-binding domains of several transcription factors have been described as targets of oxidative stress. However, recent studies described here suggest that more attention should be given to transactivating domains that may represent biologically relevant redox targets of cellular signaling. (C) 2001 Elsevier Science Inc. All rights reserved.