Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects.
Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects.
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DOI：
10.1021/acs.chemrestox.6b00256
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发表时间：
2017-01-17
影响因子：
4.1
通讯作者：
Dunlap T
中科院分区：
文献类型：
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作者：
Bolton JL;Dunlap T
醌类化合物是一类毒性中间体，在体内可产生多种危害作用，包括急性细胞毒性、免疫毒性和致癌作用。相反，醌类可通过诱导解毒酶、抗炎活性和修饰氧化还原状态来诱导细胞保护。醌类引起这些效应的机制可能相当复杂。醌的各种生物靶点取决于它们的形成速率和位置以及它们的反应性。醌是通过多种机制形成的，从由多种氧化酶和金属离子催化的儿茶酚/对苯二酚的简单氧化到涉及初始P450催化的羟基化反应随后双电子氧化的更复杂机制。醌类是迈克尔受体，细胞过程的修饰可以通过关键细胞蛋白质和/或DNA的烷基化发生。或者，醌是高度氧化还原活性的分子，其可以与它们的半醌自由基阴离子进行氧化还原循环，导致形成活性氧物质（ROS），包括超氧化物、过氧化氢和最终的羟基自由基。ROS的产生可以通过形成氧化的细胞大分子（包括脂质、蛋白质和DNA）来改变细胞内的氧化还原平衡。这一观点探讨了醌类的各种生物学靶点，包括GSH、NADPH、蛋白巯基[热休克蛋白、P450、环氧合酶-2（考克斯-2）、谷胱甘肽S-转移酶（GST）、NAD（P）H：醌氧化还原酶1（NQO 1）、Kelch样ECH相关蛋白1（Keap 1）、IκB激酶（IKK）和芳烃受体（AhR）]和DNA。证据有力地表明，醌调节的多种机制（即，烷基化对氧化应激）可以与母体化合物的已知病理学/细胞保护相关，其最好由倒U形剂量-反应曲线描述。
Quinones represent a class of toxicological intermediates, which can create a variety of hazardous effects in vivo including, acute cytotoxicity, immunotoxicity, and carcinogenesis. In contrast, quinones can induce cytoprotection through the induction of detoxification enzymes, anti-inflammatory activities, and modification of redox status. The mechanisms by which quinones cause these effects can be quite complex. The various biological targets of quinones depend on their rate and site of formation and their reactivity. Quinones are formed through a variety of mechanisms from simple oxidation of catechols/hydroquinones catalyzed by a variety of oxidative enzymes and metal ions to more complex mechanisms involving initial P450-catalyzed hydroxylation reactions followed by two-electron oxidation. Quinones are Michael acceptors, and modification of cellular processes could occur through alkylation of crucial cellular proteins and/or DNA. Alternatively, quinones are highly redox active molecules which can redox cycle with their semiquinone radical anions leading to the formation of reactive oxygen species (ROS) including superoxide, hydrogen peroxide, and ultimately the hydroxyl radical. Production of ROS can alter redox balance within cells through the formation of oxidized cellular macromolecules including lipids, proteins, and DNA. This perspective explores the varied biological targets of quinones including GSH, NADPH, protein sulfhydryls [heat shock proteins, P450s, cyclooxygenase-2 (COX-2), glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1, (NQO1), kelch-like ECH-associated protein 1 (Keap1), IκB kinase (IKK), and arylhydrocarbon receptor (AhR)], and DNA. The evidence strongly suggests that the numerous mechanisms of quinone modulations (i.e., alkylation versus oxidative stress) can be correlated with the known pathology/cytoprotection of the parent compound(s) that is best described by an inverse U-shaped dose–response curve.
影响因子：
8.8
作者：
Wangpradit O;Moman E;Nolan KB;Buettner GR;Robertson LW;Luthe G
通讯作者：
Luthe G