Calcium is a competitive inhibitor of gentamicin-renal membrane binding interactions and dietary calcium supplementation protects against gentamicin nephrotoxicity.
Calcium is a competitive inhibitor of gentamicin-renal membrane binding interactions and dietary calcium supplementation protects against gentamicin nephrotoxicity.
复制标题
钙是庆大霉素-肾膜结合相互作用的竞争性抑制剂，膳食钙补充剂可防止庆大霉素肾毒性。
DOI：
10.1172/jci111184
复制
发表时间：
1984
期刊：
影响因子：
--
通讯作者：
Weinberg,JM
中科院分区：
文献类型：
--
作者：
Humes,HD;Sastrasinh,M;Weinberg,JM
已知二价阳离子Ca++和Mg++竞争性地抑制大量氨基糖苷-膜相互作用，因此Ca++在体外急性阻止这些抗生素的神经毒性和耳毒性作用。由于庆大霉素引起的血浆和亚细胞膜损伤似乎是庆大霉素肾毒性的关键致病事件，Ca++可能在庆大霉素引起的急性肾功能衰竭中发挥类似的保护作用。为了在体内验证这种可能性，研究人员给大鼠（2组）添加4%钙（以CaCO3的形式）的饮食，以增加Ca++向肾脏的输送，并给大鼠每天皮下注射100 mg/kg庆大霉素，持续10天。与同时接受相同庆大霉素剂量和正常饮食的大鼠（1组）相比，Ca++的补充改善了庆大霉素诱导的急性肾功能衰竭。10剂量庆大霉素后，1组血尿素氮平均值为213 +/- 15 (SE)， 2组血尿素氮平均值为25 +/- 3 （P < 0.001）。尿素氮测定，1组动物肾脏排泄功能进行性下降，同时伴有肾皮质线粒体功能下降，肾皮质和线粒体钙++含量升高，钙++含量是肾小管细胞损伤程度的定量指标。口服钙离子负荷明显减轻庆大霉素引起的这些紊乱。在给药8和10次庆大霉素后，与1组相比，2组大鼠肾皮质分离的线粒体具有更高的丙酮酸-苹果酸盐、琥珀酸盐和N，N，N‘，N’-四甲基-对苯二胺-抗坏血酸盐支持的呼吸速率，更高的二硝基酚不偶联呼吸速率和更高的受体控制比。同样，在8和10次给药后，2组肾皮质和肾皮质线粒体Ca++含量显著低于1组。因此，膳食钙补充可显著防止庆大霉素诱导的肾小管细胞损伤，从而防止庆大霉素诱导的急性肾功能衰竭。Ca++的这种保护作用的机制可能与这种多阳离子抗生素与阴离子位点（主要是肾膜的酸性磷脂）相互作用的方式有关。在这方面，Ca++被发现是125i -庆大霉素结合到肾刷状边界膜（庆大霉素与肾近端小管细胞相互作用的初始位点）和125i -庆大霉素结合到磷脂酸（一种重要的膜酸性磷酸盐）的竞争性抑制剂，复合抑制常数（Ki）为12 mM
The divalent cations, Ca++ and Mg++, are known to competitively inhibit a large number of aminoglycoside-membrane interactions, so that Ca++ prevents both the neurotoxic and ototoxic effects of these antibiotics acutely in vitro. Since gentamicin-induced plasma and subcellular membrane damage appear to be critical pathogenetic events in gentamicin nephrotoxicity, Ca++ may play a similar protective role in gentamicin-induced acute renal failure. To test this possibility in vivo, rats (group 2) were given a 4% calcium (in the form of CaCO3) supplemented diet to increase delivery of Ca++ to the kidney and administered single daily subcutaneous injections of gentamicin, 100 mg/kg, for 10 d. Compared with a simultaneously studied group (group 1) of rats receiving identical gentamicin dosages and normal diets, Ca++ supplementation ameliorated gentamicin-induced acute renal failure. After 10 doses of gentamicin, blood-urea nitrogen values in group 1 averaged 213 +/- 15 (SE) and 25 +/- 3 (P less than 0.001) in group 2. The progressive decline in renal excretory function, as measured by BUN, in group 1 animals was accompanied by simultaneous declines in renal cortical mitochondrial function and elevations in renal cortex and mitochondrial Ca++ content, quantitative indices of the degree of renal tubular cell injury. Oral Ca++ loading markedly attenuated these gentamicin-induced derangements. After eight and 10 doses of gentamicin, mitochondria isolated from the renal cortex of group 2 rats had significantly higher rates of respiration supported by pyruvate-malate, succinate and N,N,N',N'-tetramethyl-p-phenyldiamine-ascorbate, higher rates of dinitrophenol-uncoupled respiration and greater acceptor control ratios than those measured in mitochondria isolated from the renal cortex of group 1 animals. Similarly, after 8 and 10 doses, renal cortex and renal cortical mitochondrial Ca++ content of group 2 was significantly lower than values observed in group 1. Thus, dietary calcium supplementation significantly protected against gentamicin-induced renal tubular cell injury and, consequently, gentamicin-induced acute renal failure. The mechanism for this protective effect of Ca++ may relate to the manner in which this polycationic antibiotic interacts with anionic sites, primarily the acidic phospholipids of renal membranes. In this regard, Ca++ was found to be a competitive inhibitor both of 125I-gentamicin binding to renal brush border membranes, the initial site of interaction between gentamicin and renal proximal tubule cells, with a composite inhibition constant (Ki) of 12 mM and of 125I-gentamicin binding to phosphatidic acid, an important membrane acidic phosph