In vitro inhibition of lysine decarboxylase activity by organophosphate esters
In vitro inhibition of lysine decarboxylase activity by organophosphate esters
复制标题
有机磷酸酯对赖氨酸脱羧酶活性的体外抑制
DOI：
10.1016/j.bcp.2014.09.011
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发表时间：
2014-12-01
影响因子：
5.8
通讯作者：
Guo, Liang-Hong
中科院分区：
文献类型：
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作者：
Wang, Sufang;Wan, Bin;Guo, Liang-Hong
有机磷酸酯（OPE）是有机磷阻燃剂的主要类别，被认为是引起健康问题的新兴环境污染物。氨基酸脱羧酶催化氨基酸转化为细胞增殖、肥大和组织生长所必需的多胺。本文利用经济且无标记的荧光传感器和细胞测定法定量评估了 12 种带有芳香族、烷基或氯代烷基取代基的 OPE 对赖氨酸脱羧酶 (LDC) 活性的抑制作用。该传感器包含大环主体（葫芦[7]脲）和荧光染料（吖啶橙）报道分子。发现 12 种 OPE 抑制 LDC 活性的能力各不相同。烷基取代的OPEs没有抑制作用。相比之下，六种芳香族或氯化烷基取代的OPE显着抑制LDC活性，IC50范围为1.32μM至9.07μM。其中，磷酸三间甲苯酯（TCrP）作为抑制剂的抑制效果甚至比LDC体内天然抑制剂鸟苷5'-二磷酸-3'-二磷酸（ppGpp）（1.60μM）更有效。此外，在非细胞毒性浓度下，这六种 OPE 对 PC12 活细胞中的 LDC 活性表现出明显的抑制作用，并导致尸胺含量显着下降。 LDC/OPE复合物的分子对接分析表明，不同的结合模式导致其抑制效果不同。我们的研究结果表明，LDC 作为 OPEs 的一个新的潜在生物学靶点，可能与 OPEs 的毒理学和致病机制有关。 (C) 2014 Elsevier Inc. 保留所有权利。
Organophosphate esters (OPEs), a major group of organophosphorus flame retardants, are regarded as emerging environmental contaminants of health concern. Amino acid decarboxylases catalyze the conversion of amino acids into polyamines that are essential for cell proliferation, hypertrophy and tissue growth. In this paper, inhibitory effect of twelve OPEs with aromatic, alkyl or chlorinated alkyl substituents on the activity of lysine decarboxylase (LDC) was assessed quantitatively with an economic and label-free fluorescence sensor and cell assay. The sensor comprises a macrocyclic host (cucurbit[7]uril) and a fluorescent dye (acridine orange) reporter. The twelve OPEs were found to vary in their capacity to inhibit LDC activity. Alkyl group substituted OPEs had no inhibitory effect. By contrast, six OPEs substituted with aromatic or chlorinated alkyl groups inhibited LDC activity significantly with IC50 ranging from 1.32 mu M to 9.07 mu M. Among them, the inhibitory effect of tri-m-cresyl phosphate (TCrP) was even more effective as an inhibitor than guanosine 5'-diphosphate-3'-diphosphate (ppGpp) (1.60 mu M), an LDC natural inhibitor in vivo. Moreover, at non-cytotoxic concentrations, these six OPEs showed perceptible inhibitory effects on LDC activity in PC12 living cells, and led to a marked loss in the cadaverine content. Molecular docking analysis of the LDC/OPE complexes revealed that different binding modes contribute to the difference in their inhibitory effect. Our finding suggested that LDC, as a new potential biological target of OPEs, might be implicated in toxicological and pathogenic mechanism of OPEs. (C) 2014 Elsevier Inc. All rights reserved.