FREE RADICAL INTERMEDIATES OF ANTIPARASITIC DRUGS

抗寄生虫药物的自由基中间体

• 批准号: 4693235
• 负责人: R DOCAMPO
• 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/4693235
• 关键词: Trichomonas; Trypanosoma cruzi; anthelmintics; antiprotozoal agents; biotransformation; drug adverse effect; drug metabolism; electron spin resonance spectroscopy; free radicals; parasitic disease chemotherapy; trypanosomiasis

Recently it has become increasingly apparent that many reactive intermediates of xenobiotics are free radicals. The formation of free radicals, including oxygen-derived radicals, may lead to extensive cellular damage. The consequences of radical-initiated reactions may be the immediate death of the cells or may be more subtle and delayed as evidenced by the development of neoplasms. In a study of Trypanosoma cruzi (the agent of Chagas' disease), crystal violet, a triarylmethane dye widely used by blood banks to eliminate transmission of Chagas' disease by transfusion, was found to undergo a one-electron reduction to produce a carbon-centered free radical. Both radical formation and the trypanocidal action of crystal violet were enhanced by light. The photodynamic action of gentian violet in blood was apparently mediated by ascorbic acid oxidation. In addition, we demonstrated that photolysis of gentian violet in aqueous medium saturated with O2 does not generate singlet oxygen. The photodynamic action of rose bengal on T. cruzi has also been established. These observations may have important chemoprophylactic implications, since illumination of blood to be transfused may result in a better therapeutic ratio. We provided evidence for the one-electron reduction of benznidazole by T. cruzi homogenates and described differences between nifurtimox and benznidazole modes of action on T. cruzi. In addition, we provided evidence for the involvement of O2 radicals in the killing of T. cruzi by polymorphonuclear leukocytes. Finally the ability of Tritrichomonas foetus (the agent of trichomoniasis in cattle) hydrogenosomal and cytosolic fractions to generate nitroimidazole and nitrofuran anion radicals was established. These results support the role of air oxidation as a detoxification reaction for the nitroimidazoles anion radicals and the involvement of a ferredoxin in their formation. On the other hand, redox cycling of nitrofurans, with formation of high steady state concentrations of oxygen-derived radicals, might be of toxicological significance.

最近，越来越明显的是许多反应性 异种生物的中间体是自由基。 自由的形成 自由基，包括氧衍生的自由基，可能导致广泛的细胞 损害。 自由基发起反应的后果可能是 细胞立即死亡，或者可能更微妙和延迟 通过肿瘤的发展。 在锥虫锥虫的研究中 Chagas疾病的代理），Crystal Violet，一种三甲烷染料的染料 由血库通过输血来消除Chagas疾病的传播， 被发现会减少一单电子以产生以碳为中的 自由基。 激进的形成和锥虫作用 光线增强了水晶紫。 绅士的光动力动作 血液中的紫色显然是通过抗坏血酸氧化介导的。 在 此外，我们证明了绅士紫罗兰在水中的光解 用O2饱和的培养基不会产生单线氧。 这 罗斯孟加拉国对克鲁兹的光动力动作也已建立。 这些观察结果可能具有重要的化学预防性意义，因为 流血的血液照明可能会导致更好的治疗 比率。 我们提供了苯二唑单电子减少的证据 由Cruzi匀浆，描述了Nifurtimox和 苯甲酸唑的动作模式。 此外，我们提供了 O2激进分子参与杀死T. Cruzi的证据 多形核白细胞。 最后，tritrichomonas胎儿的能力 （牛中的毛诺病的药物）氢气体和胞质 产生硝基咪唑和硝基呋喃阴离子的分数是 已确立的。 这些结果支持空气氧化作为一个 硝基咪唑阴离子的解毒反应和 铁蛋白参与其形成。 另一方面，氧化还原 硝化呋喃的循环，形成高稳态浓度 氧衍生的自由基的毒理学意义可能。