过氧化物抗疟药在人血红蛋白存在下的稳定性。
Stability of peroxide antimalarials in the presence of human hemoglobin.
作者信息
Creek Darren J, Ryan Eileen, Charman William N, Chiu Francis C K, Prankerd Richard J, Vennerstrom Jonathan L, Charman Susan A
机构信息
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, 381 Royal Parade, Parkville, Victoria 3052, Australia.
出版信息
Antimicrob Agents Chemother. 2009 Aug;53(8):3496-500. doi: 10.1128/AAC.00363-09. Epub 2009 Jun 1.
Peroxide antimalarials, including artemisinin, are important for the treatment of multidrug-resistant malaria. These peroxides are known to react with iron or heme to produce reactive intermediates that are thought to be responsible for their antimalarial activities. This study investigated the potential interaction of selected peroxide antimalarials with oxyhemoglobin, the most abundant form of iron in the human body. The observed stability of artemisinin derivatives and 1,2,4-trioxolanes in the presence of oxyhemoglobin was in contrast to previous reports in the literature. Spectroscopic analysis of hemoglobin found it to be unstable under the conditions used for previous studies, and it appears likely that the artemisinin reactivity reported in these studies may be attributed to free heme released by protein denaturation. The stability of peroxide antimalarials with intact oxyhemoglobin, and reactivity with free heme, may explain the selective toxicity of these antimalarials toward infected, but not healthy, erythrocytes.
过氧化物抗疟药，包括青蒿素，对于治疗耐多药疟疾很重要。已知这些过氧化物会与铁或血红素反应生成反应性中间体，这些中间体被认为是其抗疟活性的原因。本研究调查了所选过氧化物抗疟药与氧合血红蛋白（人体中最丰富的铁形式）之间的潜在相互作用。在氧合血红蛋白存在下观察到的青蒿素衍生物和1,2,4-三氧杂环戊烷的稳定性与文献中先前的报道形成对比。对血红蛋白的光谱分析发现，在先前研究使用的条件下它不稳定，并且这些研究中报道的青蒿素反应性似乎可能归因于蛋白质变性释放的游离血红素。过氧化物抗疟药与完整氧合血红蛋白的稳定性以及与游离血红素的反应性，可能解释了这些抗疟药对受感染但未健康的红细胞的选择性毒性。
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