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首页> 外文期刊>Environmental toxicology and pharmacology >DNA damage by 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced p53-mediated apoptosis through activation of cytochrome P450/aryl hydrocarbon receptor
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DNA damage by 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced p53-mediated apoptosis through activation of cytochrome P450/aryl hydrocarbon receptor

机译：2,3,7,8-四氯二苯并-p-二恶英诱导的p53介导的细胞凋亡通过激活细胞色素P450 /芳烃受体的DNA损伤

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摘要

2,3,7,8-Tetracfdorodibenzo-p-dioxin (TCDD; polycyclic aromatic hydrocarbon) is a persistent and ubiquitous environmental contaminant that causes a wide variety of deleterious effects. In this study, the DNA damage and apoptotic activity induced by TCDD was examined using in silico and in vitro approaches. In silico study showed that conformational changes and energies involved in the binding of TCDD to cytochrome P450 1B1 (CYP1B1) were crucial for its target proteins. Moreover, activated TCDD had high affinity to bind with aryl hydrocarbon receptor (AhR), with a binding energy of -564.7 Kcal/mol. Further, TCDD-CYP1B1 complex showed strong binding affinity for caspase 3, showing a binding energy of -518.5 Kcal/mol, and the docking of caspase inhibitors in the complex showed weak interaction with low binding energy as compared to TCDD-CYP1B1 caspase complexes. Interestingly, TCDD-induced apoptosis was significantly suppressed in Ac-DEVD-CMK-pre-treated cells. The DNA damage activity of TCDD was quantified by comet tail formation and -γ-H2AX foci formation in HaCaT cells. The role of CYP1B1 and AhR in DNA damage and apoptosis was demonstrated, and clotrimazole as well as knockdown of CYP1B1 and AhR could inhibit TCDD activation and suppress DNA damage followed by apoptosis in HaCaT cells. Moreover, TCDD increased expression of p53 and PUMA and our data showed that TCDD induced DNA damage followed by p53-mediated apoptosis. This study highlights the critical role of CYP1B1 and AhR in TCDD activity and proposes that inhibition of these key molecules might serve as a potential therapeutic approach for treatment of allergy and cancer.
机译：2,3,7,8-四氟二苯并-对-二恶英（TCDD；多环芳烃）是一种持续存在的普遍存在的环境污染物，会造成多种有害影响。在这项研究中，使用计算机方法和体外方法检查了由TCDD诱导的DNA损伤和凋亡活性。在计算机研究中，涉及TCDD与细胞色素P450 1B1（CYP1B1）结合的构象变化和能量对其目标蛋白至关重要。此外，活化的TCDD具有与芳烃受体（AhR）结合的高亲和力，结合能为-564.7 Kcal / mol。此外，TCDD-CYP1B1复合物显示出对caspase 3的强结合亲和力，显示出-518.5 Kcal / mol的结合能，并且与TCDD-CYP1B1 caspase复合物相比，caspase抑制剂在复合物中的对接显示出弱的相互作用和低结合能。有趣的是，在Ac-DEVD-CMK预处理的细胞中，TCDD诱导的细胞凋亡被显着抑制。 TCDD的DNA损伤活性通过HaCaT细胞中的彗尾形成和-γ-H2AX灶形成来定量。证明了CYP1B1和AhR在DNA损伤和凋亡中的作用，克霉唑以及CYP1B1和AhR的敲除可以抑制TCDD活化并抑制DNA损伤，然后在HaCaT细胞中凋亡。此外，TCDD增加了p53和PUMA的表达，我们的数据表明TCDD诱导了DNA损伤，随后是p53介导的细胞凋亡。这项研究突出了CYP1B1和AhR在TCDD活性中的关键作用，并提出抑制这些关键分子可能成为治疗变态反应和癌症的潜在治疗方法。

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