Mason R P, Fischer V
Fed Proc. 1986 Sep;45(10):2493-9.
The oxidation of acetaminophen to the corresponding phenoxyl free radical and N-acetyl-p-benzoquinone imine by mammalian peroxidases is discussed. The acetaminophen free radical is very reactive--forming dimers, and, ultimately, melanin-like polymeric products. A model compound, leading to more stable metabolites, can be obtained by introduction of methyl groups next to the oxygen, to produce 3,5-dimethylacetaminophen. The electron spin resonance spectrum of this free radical could be completely analyzed. The phenoxyl radical of the dimethyl analog does not form polymers or bind with nucleophiles. N-Acetyl-p-benzoquinone imine, a hepatic metabolite of acetaminophen, and its analog N-acetyl-3,5-dimethyl-p-benzoquinone imine are metabolized by rat liver microsomes and NADPH to their corresponding p-aminophenoxyl free radicals. The p-aminophenoxyl free radical formation could be suppressed by the deacetylase inhibitors sodium fluoride and paraoxon. Substitution of NADPH-cytochrome P-450 reductase for rat liver microsomes eliminates the deacetylase activity and results in the direct reduction of N-acetyl-3,5-dimethyl-p-benzoquinone imine to the 3,5-dimethylacetaminophen phenoxyl free radical. Neither the acetaminophen nor the 3,5-dimethylacetaminophen phenoxyl radical reduces oxygen to form superoxide or reacts with oxygen in any other detectable way.
本文讨论了哺乳动物过氧化物酶将对乙酰氨基酚氧化为相应的苯氧基自由基和N - 乙酰 - 对 - 苯醌亚胺的过程。对乙酰氨基酚自由基具有很高的反应活性，会形成二聚体，并最终形成类似黑色素的聚合产物。通过在氧原子旁边引入甲基以生成3,5 - 二甲基对乙酰氨基酚，可以得到一种能产生更稳定代谢物的模型化合物。该自由基的电子自旋共振光谱能够得到完整分析。二甲基类似物的苯氧基自由基不会形成聚合物或与亲核试剂结合。对乙酰氨基酚的肝脏代谢产物N - 乙酰 - 对 - 苯醌亚胺及其类似物N - 乙酰 - 3,5 - 二甲基 - 对 - 苯醌亚胺被大鼠肝脏微粒体和NADPH代谢为相应的对氨基苯氧基自由基。脱乙酰酶抑制剂氟化钠和对氧磷可以抑制对氨基苯氧基自由基的形成。用NADPH - 细胞色素P - 450还原酶替代大鼠肝脏微粒体可消除脱乙酰酶活性，并导致N - 乙酰 - 3,5 - 二甲基 - 对 - 苯醌亚胺直接还原为3,5 - 二甲基对乙酰氨基酚苯氧基自由基。对乙酰氨基酚和3,5 - 二甲基对乙酰氨基酚苯氧基自由基都不会将氧还原形成超氧化物，也不会以任何其他可检测的方式与氧发生反应。
