PHENYL RADICAL FORMATION BY OXYHEMOGLOBIN FROM PHENYLHYDRAZINE IN VIVO

体内苯肼的氧合血红蛋白形成苯基自由基

• 批准号: 3918695
• 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/3918695
• 关键词: drug adverse effect; electron spin resonance spectroscopy; ethanol; free radicals; hemoglobin; hemolysis; hemolytic anemia; hydralazine; isoniazid; laboratory rat; phenelzine; phenylhydrazines

The reaction of oxyhemoglobin with phenylhydrazine has received considerable attention for many decades. The basis for this interest stems from the ability of phenylhydrazine and hydrazine- based drugs to induce hemolytic anemia. Considerable evidence obtained from in vitro electron spin resonance (ESR) experiments implicates free radicals in the events leading to red blood cell hemolysis. However, until this report, no corroborating ESR evidence for in vivo free radical formation has been presented. We have successfully employed ESR to detect the formation of a radical adduct in the blood of rats which received an intragastric dose of phenylhydrazine followed by an intraperitoneal injection of the spin trap 5-5-dimethyl-I-pyrroline N-oxide (DMPO). The results of a series of experiments with sulfhydryl reagents and C- 13-labelled phenylhydrazine led us to assign this DMPO radical adduct to the trapping of a hemoglobin-derived thiyl free radical. In addition to phenylhydrazine the hydrazine-based drugs isoniazid, iproniazid, phenelzine, and hydralazine were examined. Of the four drugs, only phenelzine and iproniazid were able to induce the formation of the DMPO/hemoglobin thiyl free radical adduct in vivo, whereas able phenelzine and hydralazine were able to form this adduct in vitro. We were able to decrease the in vivo iproniazid- induced adduct formation by pretreating the rats with bis-para- nitrophenylphosphate, an arylamidase inhibitor. Our results support the idea that iproniazid is hydrolyzed in the liver to a more reactive metabolite, most likely isopropylhydrazine, which is subsequently released into the blood stream.

氧合血红蛋白与苯肼的反应 几十年来备受关注。 这样做的基础 兴趣源于苯肼和肼的能力- 诱发溶血性贫血的药物。 大量证据 从体外电子自旋共振 (ESR) 实验获得 表明自由基与导致红细胞生成的事件有关 溶血。 然而，直到本报告发布之前，还没有证实 ESR 已经提出了体内自由基形成的证据。 我们已经成功地利用 ESR 来检测 接受胃内注射的大鼠血液中的自由基加合物 腹腔注射苯肼剂量 自旋陷阱 5-5-二甲基-I-吡咯啉 N-氧化物 (DMPO)。 这 使用巯基试剂和 C- 进行一系列实验的结果 13-标记的苯肼使我们指定了这个 DMPO 基团 捕获血红蛋白衍生的硫基自由基的加合物。 除苯肼外，肼类药物异烟肼， 检查了异丙烟肼、苯乙肼和肼屈嗪。 四人之中 药物中，只有苯乙肼和异丙烟肼能够诱发 体内DMPO/血红蛋白硫基自由基加合物的形成， 而苯乙肼和肼屈嗪能够形成这种 体外加合物。 我们能够减少体内异丙烟肼- 通过用双对-预处理大鼠诱导加合物形成 硝基苯磷酸酯，一种芳基​​酰胺酶抑制剂。 我们的成果 支持异丙烟肼在肝脏中水解成 更具反应性的代谢物，最有可能是异丙肼， 随后释放到血流中。