Quinone Methide Bioactivation Pathway: Contribution to Toxicity and/or Cytoprotection?
Quinone Methide Bioactivation Pathway: Contribution to Toxicity and/or Cytoprotection?
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DOI：
10.2174/138527281801140121123046
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发表时间：
2014-01-01
影响因子：
2.6
通讯作者：
Bolton JL
中科院分区：
文献类型：
--
作者：
Bolton JL
2-或4-烷基苯酚直接2电子氧化、邻苯二酚异构化或消除好的离开基团所形成的甲基苯醌(QMS)可以解释几种药物、天然产物以及内源性化合物的细胞毒性/细胞保护作用。例如，抗逆转录病毒药物奈韦拉平和抗糖尿病药物曲格列酮都通过与甲基苯醌形成有关的机制诱导特殊的肝毒性。麻醉剂苯环利定可能通过对大脑中关键大分子的共价修饰而引起心理副作用。选择性雌激素受体调节剂(SERM)，如他莫昔芬、托瑞米芬和雷洛昔芬被代谢为甲基苯醌，这可能有助于子宫内膜的致癌作用和/或诱导解毒酶，并增强这些SERM的化学预防作用。雌激素替代制剂中存在的内源性雌激素和/或雌激素也被代谢为儿茶酚，并进一步氧化为邻苯二酚，邻苯二酚可异构化为苯二酚。这两种雌激素藜麦都可能导致DNA损伤，从而增加激素依赖型癌症的风险。天然产物，如食品和调味剂丁香酚，可以直接氧化成一种甲基苯醌，这可能解释了这种天然化合物的毒性作用。与咀嚼槟榔有关的口服毒性可能是暴露在羟基查维考中的结果，羟查维考最初被氧化成邻苯二酚，邻苯二酚异构化为对苯二酚甲醚。在评估这些天然产物的风险-效益评估时，普遍存在的类黄酮类Qercetin也有类似邻苯二酚和对苯二酚甲基异构化反应的报道。这些喹酮甲基化合物与蛋白质、DNA的反应和/或由此引起的基因表达的调节可能解释了母体化合物的毒性和/或有益作用。
The formation of quinone methides (QMs) from either direct 2-electron oxidation of 2- or 4-alkylphenols, isomerization of o-quinones, or elimination of a good leaving group could explain the cytotoxic/cytoprotective effects of several drugs, natural products, as well as endogenous compounds. For example, the antiretroviral drug nevirapine and the antidiabetic agent troglitazone both induce idiosyncratic hepatotoxicity through mechanisms involving quinone methide formation. The anesthetic phencyclidine induces psychological side effects potentially through quinone methide mediated covalent modification of crucial macromolecules in the brain. Selective estrogen receptor modulators (SERMs) such as tamoxifen, toremifene, and raloxifene are metabolized to quinone methides which could potentially contribute to endometrial carcinogenic properties and/or induce detoxification enzymes and enhance the chemopreventive effects of these SERMs. Endogenous estrogens and/or estrogens present in estrogen replacement formulations are also metabolized to catechols and further oxidized to o-quinones which can isomerize to quinone methides. Both estrogen quinoids could cause DNA damage which could enhance hormone dependent cancer risk. Natural products such as the food and flavor agent eugenol can be directly oxidized to a quinone methide which may explain the toxic effects of this natural compound. Oral toxicities associated with chewing areca quid could be the result of exposure to hydroxychavicol through initial oxidation to an o-quinone which isomerizes to a p-quinone methide. Similar o-quinone to p-quinone methide isomerization reactions have been reported for the ubiquitous flavonoid quercetin which needs to be taken into consideration when evaluating risk-benefit assessments of these natural products. The resulting reaction of these quinone methides with proteins, DNA, and/or resulting modulation of gene expression may explain the toxic and/or beneficial effects of the parent compounds.
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影响因子：
4.1
作者：
Dunlap T;Piyankarage SC;Wijewickrama GT;Abdul-Hay S;Vanni M;Litosh V;Luo J;Thatcher GR
通讯作者：
Thatcher GR
影响因子：
4.7
作者：
Chen, CL;Chi, CW;Liu, TY
通讯作者：
Liu, TY
影响因子：
4.7
作者：
Bodell, WJ;Ye, QP;Pongracz, K
通讯作者：
Pongracz, K
影响因子：
4.1
作者：
Boersma, MG;Vervoort, J;Rietjens, IMCM
通讯作者：
Rietjens, IMCM
影响因子：
4.1
作者：
Driscoll, James P.;Kornecki, Katherine;O'Donnell, John P.
通讯作者：
O'Donnell, John P.