Mitochondrial antibiograms in personalized medicine
Mitochondrial antibiograms in personalized medicine
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DOI：
10.1093/hmg/dds517
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发表时间：
2013-03-15
影响因子：
3.5
通讯作者：
Ruiz-Pesini, Eduardo
中科院分区：
文献类型：
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作者：
Pacheu-Grau, David;Gomez-Duran, Aurora;Ruiz-Pesini, Eduardo
一些核糖体抗生素在临床实践中用于对抗病原菌，可引起患者严重的药物不良反应。对抗生素的敏感性是一个多因素的性状，但敏感个体对药物脱靶效应的遗传变异可能是导致这种情况的因素之一。因此，线粒体的蛋白质合成装置由于其内共生起源而与细菌的蛋白质合成装置相似，因此线粒体核糖体经常是这些抗生素的非预期脱靶。由于药物基因组学的流行病学研究的局限性，我们构建了25 transmitochondrial细胞系，使用血小板属于高频欧洲线粒体DNA（mtDNA）单倍型组的个人和生长在不存在或存在常用的核糖体抗生素。接下来，我们分析了线粒体蛋白质的合成和线粒体耗氧量，以确定核糖体药物的一些副作用是否是由于它们与特定mtDNA单倍型组定义多态性的相互作用。利奈唑胺给药后，在携带高频率m.3010A等位基因的胞质杂种中，线粒体翻译产物的量、p. MT-CO 1/琥珀酸脱氢酶亚基A比值和呼吸复合物IV量与柠檬酸合酶（CS）比活性的比值显著降低。这些结果表明，线粒体DNA图谱应实施至少最常见的线粒体核糖体RNA（rRNA）多态性和多态性的组合和最常用的核糖体抗生素。通过这种方式，我们将获得用于抗生素治疗的个性化条形码，避免抗生素的副作用，并实现适当的个性化药物。
Some ribosomal antibiotics used in clinical practice to fight pathogenic bacteria can provoke serious adverse drug reactions in patients. Sensitivity to the antibiotics is a multifactorial trait but the genetic variation of sensitive individuals to off-target effects of the drugs might be one of the factors contributing to this condition. Thus, the protein synthesis apparatus of mitochondria is similar to that of bacteria because of its endosymbiotic origin and, therefore, mitochondrial ribosomes are frequently unintended off-targets of these antibiotics. Because of the limitations of epidemiologic studies of pharmacogenomics, we constructed 25 transmitochondrial cell lines using platelets from individuals belonging to high-frequency European mitochondrial DNA (mtDNA) haplogroups and grew them in the absence or presence of commonly used ribosomal antibiotics. Next, we analyzed the mitochondrial synthesis of proteins and the mitochondrial oxygen consumption to ascertain whether some side effects of ribosomal drugs are due to their interaction with particular mtDNA haplogroup-defining polymorphisms. The amount of mitochondrial translation products, the p.MT-CO1/succinate dehydrogenase subunit A ratio and the ratio of respiratory complex IV quantity to citrate synthase (CS)-specific activity were significantly lower, after the treatment with linezolid, in cybrids harboring the highly frequent m.3010A allele. These results suggest that mitochondrial antibiograms should be implemented for at least the most frequent mitochondrial ribosomal RNA (rRNA) polymorphisms and combinations of polymorphisms and the most frequently used ribosomal antibiotics. In this way, we would obtain individualized barcodes for antibiotic therapy, avoid the side effects of the antibiotics and enable appropriate personalized medicine.