Benzene metabolites antagonize etoposide-stabilized cleavable complexes of DNA topoisomerase IIα
Benzene metabolites antagonize etoposide-stabilized cleavable complexes of DNA topoisomerase IIα
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DOI：
10.1182/blood.v98.3.830
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发表时间：
2001-08-01
期刊：
影响因子：
20.3
通讯作者：
Kroll, DJ
中科院分区：
文献类型：
--
作者：
Baker, RK;Kurz, EU;Kroll, DJ
慢性接触苯与血液毒性和急性髓系白血病有关。拓扑异构酶IIα(TOPO 11)的抑制与苯诱导的细胞遗传学异常的发生有关。本研究旨在探讨苯代谢物抑制Topo 11的机制。在DNA切割/松弛实验中，对苯二酚和对苯二酚分别在10um和10um对Topo 11产生抑制作用。在过氧化物酶活性上，4，4‘-联苯二酚、对苯二酚和邻苯二酚分别在10um、10um和30um时表现出抑制作用。但是，在任何情况下都没有观察到可切割的复合体的稳定，代谢物似乎在酶循环的早期阶段起作用。为了支持这一结论，几种代谢物拮抗依托泊苷稳定的可切割复合体的形成，并抑制Topo R-DNA结合。因此，苯诱导的急性髓细胞白血病不太可能源于致白血病的Topo 11可裂解复合体稳定的抗肿瘤药物的事件。(C)2001年，由美国血液病学会提供。
Chronic exposure to benzene is associated with hematotoxicity and acute myelogenous leukemia. Inhibition of topoisomerase II alpha (topo 11) has been implicated in the development of benzene-induced cytogenetic aberrations. The purpose of this study was to determine the mechanism of topo 11 inhibition by benzene metabolites. In a DNA cleavage/relaxation assay, topo 11 was inhibited by p-benzoquinone and hydroquinone at 10 muM and 10 muM, respectively. On peroxidase activation, Inhibition was seen with 4,4'-biphenol, hydroquinone, and catechol at 10 muM, 10 muM, and 30 muM, respectively. But, In no case was cleavable complex stabilization observed and the metabolites appeared to act at an earlier step of the enzyme cycle. In support of this conclusion, several metabolites antagonized etoposide-stabilized cleavable complex formation and Inhibited topo R-DNA binding. It is therefore unlikely that benzene-induced acute myelogenous leukemia stems from events Invoked for leukemogenic topo 11 cleavable complex-stabilizing antitumor agents. (C) 2001 by The American Society of Hematology.