Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Chidambaram, Tamil Nadu, 608 002, India.
Center of Advanced Studies in Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600 025, India.
Mol Cell Biochem. 2018 Jan;437(1-2):1-12. doi: 10.1007/s11010-017-3091-0. Epub 2017 Jun 5.
In the present study, we investigated the effect of allyl isothiocyanate (AITC) on liver detoxification signaling pathway in 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis. Mammary tumor was induced by a single dose of DMBA (25 mg/rat) injected subcutaneously near the mammary gland in Sprague-Dawley rats. DMBA-alone-treated rats show an increased synthesis of phase I detoxification enzymes, lipid peroxidative markers, liver marker enzymes, and lipid profiles whereas, depletion of phase II detoxification enzymes and antioxidants in rat liver tissues. Oral administration of AITC restored the levels of biochemical markers in DMBA-treated rats. Furthermore, histopathological results also confirmed that AITC protects DMBA-mediated hepatocellular damage. We also observed that AITC treatment significantly downregulates AhR and upregulates the expression of Nrf2 in DMBA-treated rats. The binding efficacy of AITC with AhR and Nrf2 analysis by molecular docking studies reveals that AITC has strong interaction with AhR and Nrf2 proteins through hydrogen and hydrophobic interactions. Thus, AITC prevents DMBA-induced mammary carcinogenesis via inhibition of phase I and induction of phase II detoxification enzymes by modulating AhR/Nrf2 signaling pathway.
在本研究中，我们研究了丙烯基异硫氰酸酯（AITC）对 7,12-二甲基苯并（a）蒽（DMBA）诱导的乳腺致癌作用中肝脏解毒信号通路的影响。通过在 Sprague-Dawley 大鼠乳腺附近皮下注射单次剂量的 DMBA（25mg/大鼠）诱导乳腺肿瘤。DMBA 单独处理的大鼠表现出 I 相解毒酶、脂质过氧化标志物、肝标志物酶和脂质谱的合成增加，而大鼠肝组织中 II 相解毒酶和抗氧化剂的耗竭。AITC 的口服给药恢复了 DMBA 处理大鼠的生化标志物水平。此外，组织病理学结果也证实 AITC 可保护 DMBA 介导的肝细胞损伤。我们还观察到，AITC 处理可显著下调 AhR 并上调 DMBA 处理大鼠中 Nrf2 的表达。通过分子对接研究对 AITC 与 AhR 和 Nrf2 蛋白的结合效力进行分析，结果表明 AITC 通过氢键和疏水相互作用与 AhR 和 Nrf2 蛋白具有很强的相互作用。因此，AITC 通过抑制 I 相并通过调节 AhR/Nrf2 信号通路诱导 II 相解毒酶，防止 DMBA 诱导的乳腺致癌作用。
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