Problematic detoxitication of estrogen quinones by NAD(P)H-dependent quinone oxidoreductase and glutathione-S-transferase
Problematic detoxitication of estrogen quinones by NAD(P)H-dependent quinone oxidoreductase and glutathione-S-transferase
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DOI：
10.1021/tx8000797
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发表时间：
2008-07-01
影响因子：
4.1
通讯作者：
Thatcher, Gregory R. J.
中科院分区：
文献类型：
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作者：
Chandrasena, R. Esala P.;Edirisinghe, Praneeth D.;Thatcher, Gregory R. J.
月经初潮早期、更年期晚期和激素替代疗法导致的雌激素暴露增加了激素依赖性癌症的风险因素。虽然分子机制尚未完全确定，但来自雌激素氧化代谢的醌类亲电反应中间体对DNA的损伤与此密切相关。目前的假设是4-羟孕酮-醌（4-OQE）作为近端雌激素致癌物质，通过Michael加成形成去嘌呤DNA加合物。该假说的一个方面假设NAD(P) h依赖的醌氧化还原酶（NQO1）在减少4-OQE和防止雌激素致癌作用中起关键作用，尽管有两篇报道称4-OQE不是NQO1的底物。4-OQE被谷胱甘肽快速有效地捕获，允许在NQO1存在和不存在的情况下测量4-OQE的nadph依赖性还原，4-OQE被观察到是NQO1的底物，但NQO1对nadph依赖性还原的加速度小于非酶反应的10倍，在更相关的纳摩尔浓度的底物下小于2倍。另一种解毒酶，谷胱甘肽- s -转移酶，被观察到是4-OQE的靶标，迅速进行共价修饰。这些结果表明，NQO1和GST在4-羟基雌激素醌直接解毒中的关键作用是有问题的。
Estrogen exposure through early menarche, late menopause, and hormone replacement therapy increases the risk factor for hormone-dependent cancers. Although the molecular mechanisms are not completely established, DNA damage by quinione electrophilic reactive intermediates, derived from estrogen oxidative metabolism, is strongly implicated. A current hypothesis has 4-hydroxyestrone-o-quinone (4-OQE) acting as the proximal estrogen carcinogen, forming depurinating DNA adducts via Michael addition. One aspect of this hypothesis posits a key role for NAD(P)H-dependent quinone oxidoreductase (NQO1) in the reduction of 4-OQE and protection against estrogen carcinogenesis, despite two reports that 4-OQE is not a substrate for NQO1. 4-OQE is rapidly and efficiently trapped by GSH, allowing measurement of NADPH-dependent reduction of 4-OQE in the presence and absence of NQO1 4-OQE was observed to be a substrate for NQO1, but the acceleration of NADPH-dependent reduction by NQO1 over the nonenzymic reaction is less than 10-fold and at more relevant nanomolar concentrations of substrate is less than 2-fold. An alternative detoxifying enzyme, glutathione-S-transferase, was observed to be a target for 4-OQE, rapidly undergoing covalent modification. These results indicate that a key role for NQO1 and GST in direct detoxification of 4-hydroxy-estrogen quinones is problematic.