Larsson R, Ross D, Nordenskjöld M, Lindeke B, Olsson L I, Moldéus P
Chem Biol Interact. 1984 Nov;52(1):1-14. doi: 10.1016/0009-2797(84)90079-6.
The nature of the reactive metabolites formed during HRP/H2O2 catalyzed oxidation of p-phenetidine was investigated. Interaction with DNA measured as the induction of DNA single strand breaks and DNA binding resulted in a time-dependent decrease in the interaction and could be related to the primary oxidation of p-phenetidine. Oxygen uptake observed during p-phenetidine metabolism in the presence of GSH also exhibited such a correlation. GSH-conjugate formation and protein binding on the other hand exhibited an initial increase and did not appear to be directly related to primary p-phenetidine oxidation since maximal interaction was obtained when p-phenetidine had been completely metabolized. The GSH-conjugate and protein binding ratio of ring labelled to ethyl labelled p-phenetidine of approx. 2:1 indicated that these reactive metabolites(s) may be dimer(s) whose formation presumably involved loss of one ethoxy group of p-phenetidine. Accordingly formation of ethanol, indicative of ethoxy group elimination, could be observed during p-phenetidine metabolism. Only one metabolite generated from p-phenetidine oxidation exhibited a concentration dependent binding to protein. This metabolite also reacted with GSH to form water-soluble conjugates. Prior reduction of the metabolite by ascorbic acid prevented this conjugate formation. The mass spectral fragmentation pattern of the reactive protein- and GSH-binding metabolite was compatible with the structure N(4-ethoxyphenyl)-p-benzoquinoneimine.
研究了在辣根过氧化物酶/过氧化氢催化对乙氧基苯胺氧化过程中形成的反应性代谢产物的性质。以DNA单链断裂的诱导和DNA结合来衡量的与DNA的相互作用导致相互作用随时间下降，这可能与对乙氧基苯胺的初级氧化有关。在谷胱甘肽存在下对乙氧基苯胺代谢过程中观察到的氧摄取也表现出这种相关性。另一方面，谷胱甘肽共轭物的形成和蛋白质结合最初增加，并且似乎与对乙氧基苯胺的初级氧化没有直接关系，因为当对乙氧基苯胺完全代谢时获得了最大相互作用。环标记与乙基标记的对乙氧基苯胺的谷胱甘肽共轭物与蛋白质结合的比例约为2:1，表明这些反应性代谢产物可能是二聚体，其形成可能涉及对乙氧基苯胺一个乙氧基的损失。因此，在对乙氧基苯胺代谢过程中可以观察到乙醇的形成，这表明乙氧基被消除。对乙氧基苯胺氧化产生的只有一种代谢产物表现出与蛋白质的浓度依赖性结合。这种代谢产物也与谷胱甘肽反应形成水溶性共轭物。用抗坏血酸预先还原该代谢产物可防止这种共轭物的形成。反应性蛋白质和谷胱甘肽结合代谢产物的质谱裂解模式与N(4-乙氧基苯基)-对苯醌亚胺的结构相符。
