Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain.
Toxicol Sci. 2011 Feb;119(2):245-56. doi: 10.1093/toxsci/kfq267. Epub 2010 Sep 9.
Gentamicin is an aminoglycoside antibiotic widely used against infections by Gram-negative microorganisms. Nephrotoxicity is the main limitation to its therapeutic efficacy. Gentamicin nephrotoxicity occurs in 10-20% of therapeutic regimes. A central aspect of gentamicin nephrotoxicity is its tubular effect, which may range from a mere loss of the brush border in epithelial cells to an overt tubular necrosis. Tubular cytotoxicity is the consequence of many interconnected actions, triggered by drug accumulation in epithelial tubular cells. Accumulation results from the presence of the endocytic receptor complex formed by megalin and cubulin, which transports proteins and organic cations inside the cells. Gentamicin then accesses and accumulates in the endosomal compartment, the Golgi and endoplasmic reticulum (ER), causes ER stress, and unleashes the unfolded protein response. An excessive concentration of the drug over an undetermined threshold destabilizes intracellular membranes and the drug redistributes through the cytosol. It then acts on mitochondria to unleash the intrinsic pathway of apoptosis. In addition, lysosomal cathepsins lose confinement and, depending on their new cytosolic concentration, they contribute to the activation of apoptosis or produce a massive proteolysis. However, other effects of gentamicin have also been linked to cell death, such as phospholipidosis, oxidative stress, extracellular calcium-sensing receptor stimulation, and energetic catastrophe. Besides, indirect effects of gentamicin, such as reduced renal blood flow and inflammation, may also contribute or amplify its cytotoxicity. The purpose of this review was to critically integrate all these effects and discuss their relative contribution to tubular cell death.
庆大霉素是一种氨基糖苷类抗生素，广泛用于治疗革兰氏阴性微生物感染。肾毒性是其治疗效果的主要限制因素。在 10-20%的治疗方案中，庆大霉素会引起肾毒性。庆大霉素肾毒性的一个主要方面是其肾小管效应，它可能从上皮细胞的刷状缘丧失到明显的肾小管坏死。肾小管细胞毒性是许多相互关联的作用的结果，这些作用是由药物在肾小管上皮细胞中的积累引发的。由于存在由巨球蛋白和 cubulin 组成的内吞受体复合物，药物的积累导致了药物的积累，该复合物将蛋白质和有机阳离子运入细胞内。然后，庆大霉素进入并在内涵体区室、高尔基体和内质网 (ER) 中积累，导致 ER 应激，并引发未折叠蛋白反应。药物在未确定的阈值上的浓度超过一定限度，会破坏细胞内的膜，使药物在细胞质中重新分布。然后，它作用于线粒体，引发细胞凋亡的内在途径。此外，溶酶体组织蛋白酶失去限制，并且根据它们在细胞质中的新浓度，它们有助于凋亡的激活或产生大量蛋白水解。然而，庆大霉素的其他作用也与细胞死亡有关，如磷脂病、氧化应激、细胞外钙敏感受体刺激和能量灾难。此外，庆大霉素的间接作用，如减少肾血流量和炎症，也可能有助于或放大其细胞毒性。本综述的目的是批判性地整合所有这些作用，并讨论它们对肾小管细胞死亡的相对贡献。
