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.

中文翻译：

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醌甲基化物生物激活途径：对毒性和/或细胞保护的贡献？


2-或4-烷基酚的直接2电子氧化、邻醌的异构化或良好离去基团的消除形成醌甲基化物（QM）可以解释几种药物、天然产物、以及内源性化合物。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均通过涉及醌甲基化物形成的机制诱导特殊肝毒性。麻醉剂苯环己哌啶可能通过醌甲基化物介导的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，代谢为醌甲基化物，可能导致子宫内膜致癌特性和/或诱导解毒酶并增强这些 SERM 的化学预防作用。内源性雌激素和/或雌激素替代制剂中存在的雌激素也代谢为儿茶酚并进一步氧化为邻醌，邻醌可异构化为醌甲基化物。两种雌激素醌类化合物都可能导致 DNA 损伤，从而增加激素依赖性癌症风险。食品和风味剂丁子香酚等天然产物可以直接氧化成醌甲基化物，这可以解释这种天然化合物的毒性作用。与咀嚼槟榔相关的口腔毒性可能是由于接触羟基胡椒粉酚，首先氧化成邻醌，然后异构化为对醌甲基化物。 据报道，普遍存在的类黄酮槲皮素也存在类似的邻醌与对醌甲基化物异构化反应，在评估这些天然产物的风险效益评估时需要考虑到这一点。这些醌甲基化物与蛋白质、DNA 的反应和/或基因表达的调节可以解释母体化合物的毒性和/或有益作用。