Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstraße 30, 48149 Münster, Germany.
Anal Bioanal Chem. 2013 Jun;405(15):5249-58. doi: 10.1007/s00216-013-6929-7. Epub 2013 Apr 4.
Melarsoprol is the only currently available drug for treatment of the late stage of African trypanosomiasis (sleeping sickness). Unfortunately, the arsenic-containing drug causes serious side effects, for which the mechanisms have not been elucidated so far. This investigation describes the study of the melarsoprol biotransformation processes by electrochemical (EC) techniques. Based on EC, potential oxidation reactions of melarsoprol are examined. Moreover, the reactivity of melarsoprol, its metabolite melarsen oxide, and their oxidation products toward the tripeptide glutathione and the proteins hemoglobin and human serum albumin is evaluated. The combination of different analytical techniques allows the identification as well as the quantification of the biotransformation products. The hyphenation of liquid chromatography (LC) and electrospray ionization mass spectrometry (ESI-MS) is applied for identification and structure elucidation, which implies the determination of exact masses and fragmentation patterns. For the selective detection of arsenic containing metabolites, LC coupled to inductively coupled plasma mass spectrometry is utilized. Based on the obtained data, the oxidative biotransformation of melarsoprol can be predicted, revealing novel species which have been suspected, but not been identified up to now. The results of the protein studies prove that melarsen oxide, the active derivative of melarsoprol, strongly binds to human hemoglobin and forms different adducts via the free cysteinyl groups of the hemoglobin α- and β-chain.
美拉胂醇是目前唯一可用于治疗非洲锥虫病（昏睡病）晚期的药物。不幸的是，这种含砷药物会引起严重的副作用，但迄今为止其机制尚未阐明。本研究通过电化学（EC）技术描述了美拉胂醇生物转化过程的研究。基于 EC，检查了美拉胂醇的潜在氧化反应。此外，还评估了美拉胂醇、其代谢产物美拉胂肟及其氧化产物与三肽谷胱甘肽以及血红蛋白和人血清白蛋白的反应性。不同分析技术的结合允许鉴定和定量生物转化产物。将液相色谱（LC）和电喷雾电离质谱（ESI-MS）联用用于鉴定和结构阐明，这意味着要确定精确质量和碎片模式。为了选择性检测含砷的代谢物，将 LC 与电感耦合等离子体质谱联用。基于获得的数据，可以预测美拉胂醇的氧化生物转化，揭示出以前怀疑但尚未确定的新物质。蛋白质研究的结果证明，美拉胂肟，美拉胂醇的活性衍生物，与人血红蛋白强烈结合，并通过血红蛋白的α-和β-链上的游离半胱氨酸残基形成不同的加合物。
