Störle C, Stettmeier K, Eyer P
Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Germany.
Free Radic Res Commun. 1992;17(2):133-41. doi: 10.3109/10715769209082270.
Aromatic amines with electron-donating substituents are directly activated by pure oxyhemoglobin with formation of ferrihemoglobin. Of these xenobiotics the N-alkylated p-phenylenediamines are particularly active. With N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) cooxidation with oxyhemoglobin was observed by ESR spectroscopy with formation of the arylaminyl free radical (TMPD+). Since the radical is rapidly reduced by ferrohemoglobin, a catalytic cycle of ferrihemoglobin formation is sustained with initially very low steady-state concentrations of the radical, e.g. below 0.1%. Ferrihemoglobin is also able to oxidize TMPD to the radical, hence the steady-state concentration of TMPD+ rises with increasing ferrihemoglobin. Radicals of the Wurster's type tend to disproportionate at high rates generating reactive quinonediiminium cations which oxidize and arylate cellular thiols like GSH and protein SH groups. Because the disproportionation rate depends on the square of the radical concentration, quenching of the radicals by ferrohemoglobin to protect cellular thiols will be effective as long as the capacity of the methemoglobin reductase system is not overwhelmed. The results indicate that erythrocytes may play a critical role in activation and detoxication of p-phenylenediamines.
带有供电子取代基的芳香胺可被纯氧合血红蛋白直接激活，形成高铁血红蛋白。在这些外源性物质中，N-烷基化对苯二胺特别活跃。对于N,N,N',N'-四甲基对苯二胺（TMPD），通过电子顺磁共振光谱观察到其与氧合血红蛋白发生共氧化反应，形成芳胺基自由基（TMPD+*）。由于该自由基会迅速被亚铁血红蛋白还原，因此在自由基的初始稳态浓度非常低（例如低于0.1%）的情况下，高铁血红蛋白形成的催化循环得以维持。高铁血红蛋白也能够将TMPD氧化为自由基，因此随着高铁血红蛋白含量的增加，TMPD+*的稳态浓度会升高。沃斯特型自由基倾向于以高速率发生歧化反应，生成具有反应活性的醌二亚胺阳离子，这些阳离子会氧化并使细胞内的硫醇（如谷胱甘肽和蛋白质巯基）发生芳基化。由于歧化反应速率取决于自由基浓度的平方，只要高铁血红蛋白还原酶系统的能力未被耗尽，亚铁血红蛋白对自由基的淬灭作用以保护细胞硫醇就会有效。结果表明，红细胞可能在对苯二胺的激活和解毒过程中发挥关键作用。
