RADICAL ANION METABOLITES

自由基阴离子代谢物

• 批准号: 4693236
• 负责人: R P MASON
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/4693236
• 关键词: NAD(H) phosphate; NADPH cytochrome c2 reductase; anions; biotransformation; chemical substitution; cytochrome P450; electron spin resonance spectroscopy; free radicals; halocarbon compound; liver; local antiinfective agents; microsomes; mitochondria; nicotinamide adenine dinucleotide; nitro compounds; nitrobenzene; toxin metabolism

The objective of this study is to determine the role played by free radicals in the reductive metabolism of xenobiotics. The anaerobic incubation of almost all nitroaromatic xenobiotics, e.g., nitrobenzene, by the microsomal, mitochondrial, or cytosolic fractions of rat liver in the presence of either NADH or NADPH, leads to a multiple-line electron spin resonance spectrum characteristic of the nitro anion free radical. We have now demonstrated nitro anion radical formation by mitochondria using endogenous cofactors. Nitro drugs do not affect mitochondrial respiration, in particular the coupling to ADP. The sites of nitro reduction, as determined by inhibitors of the mitochondrial transport chain, appear to be NADH dehydrogenase and outer-membrane NAD(P)H cytochrome c reductase. Halogen-substituted nitro compounds are radiosensitizers and are among the most toxic nitro compounds. Loss of halide by the nitroaromatic anion forms a very reactive carbon-centered free radical, detected by spin trapping, which reacts with cellular macromolecules. The irreversible binding of these nitro compounds to DNA, protein, etc. may be inhibited by spin traps. Free radical formation by hepatic microsomal cytochrome P-450 reduction of gentian violet, SO2, CCl4 and O2 has also been investigated.

本研究的目的是确定自由发挥的作用 外源物质还原代谢中的自由基。 厌氧的 几乎所有硝基芳香族异生物质（例如硝基苯）的孵育 大鼠肝脏中的微粒体、线粒体或胞质部分 NADH 或 NADPH 的存在会导致多线电子自旋 硝基阴离子自由基的共振光谱特征。 我们有 现在使用线粒体证明了硝基阴离子自由基的形成 内源性辅助因子。 硝基药物不影响线粒体呼吸， 特别是与 ADP 的耦合。 硝基还原位点如 由线粒体转运链抑制剂决定，似乎是 NADH 脱氢酶和外膜 NAD(P)H 细胞色素 c 还原酶。 卤素取代的硝基化合物是放射增敏剂，属于放射增敏剂。 毒性最强的硝基化合物。 硝基芳香族阴离子导致卤化物损失 形成非常活跃的以碳为中心的自由基，可通过自旋检测到 捕获，与细胞大分子发生反应。 不可逆转的 这些硝基化合物与 DNA、蛋白质等的结合可能会被抑制 自旋陷阱。 肝微粒体细胞色素 P-450 还原自由基形成 还对龙胆紫、SO2、CCl4 和 O2 进行了研究。