Curcumin attenuates cytochrome P450 induction in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin by ROS-dependently degrading AhR and ARNT
Curcumin attenuates cytochrome P450 induction in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin by ROS-dependently degrading AhR and ARNT
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DOI：
10.1111/j.1349-7006.2008.00984.x
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发表时间：
2008-12-01
期刊：
影响因子：
5.7
通讯作者：
Park, Jong-Wan
中科院分区：
文献类型：
--
作者：
Choi, Hyunsung;Chun, Yang-Sook;Park, Jong-Wan
TCDD（2，3，7，8-tetrachlorodibenzo-p-dioxin）是一种高毒性的环境污染物。当暴露于TCDD时，哺乳动物细胞通过异常的细胞内信号级联发生恶性转化，并且细胞色素P450（CYP 1A 1）酶的强烈诱导被认为通过产生遗传毒性代谢物介导致癌作用。我们在这里研究了姜黄素是否对TCDD诱导的细胞增殖和细胞转化具有预防活性。最初，检查细胞色素P450（CYP 1A 1）1A 1和1B 1的细胞水平，因为已知这些物质会产生介导遗传毒性应激的雌激素代谢物。姜黄素在mRNA和蛋白水平抑制TCDD诱导的CYP 1A 1和1B 1。值得注意的是，姜黄素降低了芳烃受体（AhR）和AhR核转运蛋白（ARNT）的核水平，但细胞质中的水平没有降低。研究还发现，氧化应激介导姜黄素诱导的AhR和ARNT降解。此外，在体外转化试验表明，在正常的人胚肾细胞和正常的前列腺细胞姜黄素阻止锚定非依赖性生长诱导的TCDD。总之，姜黄素减弱AhR/ARNT介导的二恶英诱导，推测这种作用模式可能是姜黄素预防恶性转化的原因。这项研究的结果应该被发现有助于开发姜黄素作为化学预防或抗癌剂的药效学研究的设计阶段。（Cancer Sci 2008; 99：2518-2524）。
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a highly toxic environmental contaminant. When exposed to TCDD, mammalian cells undergo malignant transformation via abnormal intracellular signaling cascades, and the robust inductions of cytochrome P450 (CYP) enzymes are considered to mediate carcinogenesis by producing genotoxic metabolites. We here examined whether curcumin has preventive activity against TCDD-induced CYP production and cell transformation. Initially, the cellular levels of cytochrome P450 (CYP) 1A1 and 1B1 were examined, because these are known to generate estrogen metabolites that mediate genotoxic stress. Curcumin inhibited CYP1A1 and 1B1 induction by TCDD at the mRNA and protein levels. Notably, the nuclear levels of arylhydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) were decreased by curcumin, but those in the cytoplasm were not. It was also found that oxidative stress mediated the curcumin-induced degradations of AhR and ARNT. Furthermore, in vitro transformation assays showed that in normal human embryonic kidney cells and normal prostate cells curcumin prevents the anchorage-independent growth induced by TCDD. In conclusion, curcumin attenuates AhR/ARNT-mediated CYP induction by dioxin and presumably this mode-of-action may be responsible for the curcumin prevention of malignant transformation. The findings of this study should be found helpful in the design stage of pharmacodynamic studies for developing curcumin as a chemopreventive or anticancer agent. (Cancer Sci 2008; 99: 2518-2524).