Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Signal Transduction and Molecular Haematology, Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium; de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
Int J Antimicrob Agents. 2019 Nov;54(5):661-667. doi: 10.1016/j.ijantimicag.2019.07.021. Epub 2019 Jul 30.
Thrombocytopenia is commonly seen in patients receiving linezolid for >14 days. Linezolid is a reversible inhibitor of mitochondrial function in various cell types. This study investigated the inhibitory effects of linezolid and tedizolid, and their potential recovery on (i) CYTox I expression (subunit I of cytochrome c-oxidase; encoded by the mitochondrial genome), (ii) cytochrome c-oxidase activity and (iii) mitochondrial respiration (Seahorse bioanalysis) in two megakaryocytic cell lines [UT-7 WT (human acute megakaryoblastic leukaemia cells) and UT-7 MPL (transduced to express the thrombopoietin receptor)]. Cells were exposed to linezolid (0.5-25 mg/L) or tedizolid (0.1-5 mg/L) for up to 5 days and recovery followed after drug removal. Both oxazolidinones caused concentration- and time-dependent inhibition of CYTox I expression, cytochrome c-oxidase activity and mitochondrial spare capacity. On electron microscopy, mitochondria appeared dilated with a loss of cristae. Globally, tedizolid exerted stronger effects than linezolid. While CYTox I expression recovered completely after 6 days of drug washout, only partial (linezolid) or no (tedizolid) recovery of cytochrome c-oxidase activity, and no rescue of mitochondrial spare capacity (after 3 days) was observed. Thus, and in contrast to previous studies using a variety of cell lines unrelated to megakaryocytic lineages, the inhibitory effects exerted by oxazolidinones on the mitochondrial function of megakaryoblastic cells appear to be particularly protracted. Given the dynamics of platelet production and destruction, these results may explain why oxazolidinone-induced thrombocytopenia is one of the most common side effects in patients exposed to these antibiotics.
血小板减少症在接受利奈唑胺治疗>14 天的患者中很常见。利奈唑胺是各种细胞类型中线粒体功能的可逆抑制剂。本研究调查了利奈唑胺和替加环素对（i）两种巨核细胞系[UT-7 WT（人急性巨核细胞白血病细胞）和 UT-7 MPL（转导以表达血小板生成素受体）]中 CYTox I 表达（细胞色素 c-氧化酶的亚单位 I；由线粒体基因组编码）、（ii）细胞色素 c-氧化酶活性和（iii）线粒体呼吸（ Seahorse 生物分析）的抑制作用及其潜在恢复能力。细胞暴露于利奈唑胺（0.5-25mg/L）或替加环素（0.1-5mg/L）中，最长达 5 天，然后在药物去除后进行恢复。两种唑烷酮类药物均引起 CYTox I 表达、细胞色素 c-氧化酶活性和线粒体备用能力的浓度和时间依赖性抑制。在电子显微镜下，线粒体扩张，嵴丢失。总体而言，替加环素的作用强于利奈唑胺。虽然在药物洗脱 6 天后 CYTox I 表达完全恢复，但仅观察到部分（利奈唑胺）或无（替加环素）细胞色素 c-氧化酶活性恢复，以及线粒体备用能力无恢复（3 天后）。因此，与先前使用与巨核细胞谱系无关的多种细胞系进行的研究相反，唑烷酮类药物对巨核细胞的线粒体功能的抑制作用似乎特别持久。鉴于血小板生成和破坏的动态，这些结果可能解释了为什么唑烷酮类药物引起的血小板减少症是暴露于这些抗生素的患者最常见的副作用之一。
