title: Investigation of the biotransformation of melarsoprol by electrochemistry coupled to complementary LC/ESI-MS and LC/ICP-MS analysis.
abstract: 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.
authors.affiliation: Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstraße 30, 48149 Münster, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Baumann
authors.forename: Thorben
authors.initials: T
authors.lastname: Pfeifer
authors.forename: Daniel
authors.initials: D
authors.lastname: Melles
authors.forename: Uwe
authors.initials: U
authors.lastname: Karst
mesh_terms: D001152:Arsenicals / Q000737:chemistry / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods*; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D008549:Melarsoprol / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D014344:Trypanocidal Agents / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001152:Arsenicals; D006454:Hemoglobins; D012709:Serum Albumin; D014344:Trypanocidal Agents; C044719:melarsen oxide; D008549:Melarsoprol