Rustenbeck I, Eggers G, Reiter H, Münster W, Lenzen S
Institute of Pharmacology and Toxicology, University of Göttingen, Germany.
Biochem Pharmacol. 1998 Oct 15;56(8):977-85. doi: 10.1016/s0006-2952(98)00232-9.
In this study, the regulation of mitochondrial Ca2+ transport by polyamines structurally related to spermine and by analogous polycationic compounds was characterized. Similar to spermine, a number of amino groups containing cationic compounds exerted a dual effect on Ca2+ transport of isolated rat liver mitochondria: a decrease in Ca2+ uptake velocity and an enhancement of Ca2+ accumulation. In contrast to the effects of spermine and other aliphatic polyamines, however, the accumulation-enhancing effect of aminoglucosides, basic polypeptides, and metal-amine complexes turned into an inhibition of Ca2+ accumulation at higher concentrations. Within groups of structurally related compounds, the potency to decrease Ca2+ uptake velocity and to enhance Ca2+ accumulation correlated with the number of cationic charges. The presence of multiple, distributed cationic charges was a necessary, but not sufficient criterion for effects on mitochondrial Ca2+ transport, because cationic polyamines and basic oligopeptides which did not enhance mitochondrial Ca2+ accumulation could be identified. Spermine was not able to antagonize the blocking of Ca2+ uptake by ruthenium red, but rather showed an apparent synergism, which can be explained as a displacement of membrane-bound Ca2+ by spermine. The aminoglucosides, gentamicin and neomycin, but not the inactive polyamine bis(hexamethylene)-triamine, inhibited the binding of spermine to intact mitochondria. Apparently, the binding of spermine, gentamicin, and a number of polyamine analogues to low-affinity binding sites at mitochondria, which have low, but distinct structural requirements and which may correspond to phospholipid headgroups, indirectly influences the activity state of the mitochondrial Ca2+ uniporter. The ability of aminoglucosides to displace spermine from the mitochondria and to inhibit mitochondrial Ca2+ accumulation may contribute to the mitochondrial lesions, which are known to occur early in the course of aminoglucoside-induced nephrotoxicity.
在本研究中，对与精胺结构相关的多胺及类似的聚阳离子化合物对线粒体Ca2+转运的调节作用进行了表征。与精胺类似，一些含氨基的阳离子化合物对离体大鼠肝线粒体的Ca2+转运具有双重作用：降低Ca2+摄取速度并增强Ca2+积累。然而，与精胺和其他脂肪族多胺的作用不同，氨基糖苷类、碱性多肽和金属 - 胺络合物的积累增强作用在较高浓度时转变为对Ca2+积累的抑制。在结构相关的化合物组内，降低Ca2+摄取速度和增强Ca2+积累的效力与阳离子电荷数相关。多个分布的阳离子电荷的存在是影响线粒体Ca2+转运的必要但非充分标准，因为可以鉴定出不增强线粒体Ca2+积累的阳离子多胺和碱性寡肽。精胺无法拮抗钌红对Ca2+摄取的阻断作用，反而表现出明显的协同作用，这可以解释为精胺取代了膜结合的Ca2+。氨基糖苷类药物庆大霉素和新霉素，但无活性的多胺双（六亚甲基） - 三胺则不能抑制精胺与完整线粒体的结合。显然，精胺、庆大霉素和一些多胺类似物与线粒体上低亲和力结合位点的结合，这些位点具有低但独特的结构要求且可能对应于磷脂头部基团，间接影响线粒体Ca2+单向转运体的活性状态。氨基糖苷类药物从线粒体中取代精胺并抑制线粒体Ca2+积累的能力可能导致线粒体损伤，这在氨基糖苷类药物诱导的肾毒性过程早期就已为人所知。
