Reilly C A, Aust S D
Biotechnology Center, Utah State University, Logan 84322-4705, USA.
Chem Res Toxicol. 1997 Mar;10(3):328-34. doi: 10.1021/tx960189l.
Hydrazines are believed to be oxidized by peroxidases to reactive intermediates responsible for a variety of adverse side effects including cancer and drug-induced lupus. However, hydrazines are regarded as a poor peroxidase substrates because inactivation of the peroxidase occurs during oxidation of these compounds. We have investigated the hypothesis that efficient peroxidase substrates, termed mediators, may stimulate peroxidase-catalyzed oxidation of hydrazines to intermediates capable of causing DNA damage. Oxidation of hydralazine by horseradish peroxidase was stimulated, enzyme inactivation was significantly decreased, and DNA strand breakage was enhanced by the addition of chlorpromazine. Similar results were obtained using other peroxidases, mediators, and hydrazine derivatives. DNA damage required the addition of a minimum of 3 equiv of hydrogen peroxide, suggesting the involvement of a three-electron oxidation product of hydralazine in DNA damage. Efficient substrates may therefore play a critical role in peroxidase-dependent oxidative metabolism and subsequent damage to biological macromolecules by certain chemicals.
人们认为肼类化合物会被过氧化物酶氧化为活性中间体，这些中间体导致包括癌症和药物性狼疮在内的各种不良副作用。然而，肼类被视为较差的过氧化物酶底物，因为在这些化合物氧化过程中过氧化物酶会失活。我们研究了这样一个假说，即高效的过氧化物酶底物（称为介质）可能会刺激过氧化物酶催化肼类氧化为能够导致DNA损伤的中间体。通过添加氯丙嗪，辣根过氧化物酶对肼苯哒嗪的氧化作用得到增强，酶失活显著降低，DNA链断裂增加。使用其他过氧化物酶、介质和肼衍生物也得到了类似结果。DNA损伤需要至少添加3当量的过氧化氢，这表明肼苯哒嗪的三电子氧化产物参与了DNA损伤。因此，高效底物可能在过氧化物酶依赖性氧化代谢以及随后某些化学物质对生物大分子的损伤中起关键作用。
