Ruben Z, Anderson S N, Kacew S
Department of Pathology, G.D. Searle & Company, Skokie, Illinois.
Lab Invest. 1991 Apr;64(4):574-84.
In the investigation of cellular changes associated with intracellular drug storage, we incubated cultured rabbit aorta muscle cells with various amphiphilic agents. Disobutamide, chloroquine, and desipramine each increased cellular content of rhamnose, arabinose, mannose, glucose, and total saccharides; these agents also elevated total and individual phospholipid of all classes. Amiodarone did not alter total saccharide content, but increased total phospholipid. Tilorone, in contrast, decreased total saccharides, but phospholipid content was unchanged. All test agents decreased xylose content. By light microscopy, disobutamide, chloroquine, and tilorone induced clear cytoplasmic vacuoles; desipramine induced dense cytoplasmic granules; and amiodarone induced both cytoplasmic changes. By electron microscopy, the content of the cellular alterations induced by disobutamide was primarily electron lucent; that of the alterations induced by desipramine was primarily concentric lamellar bodies/flocculent electron-dense structures; and that of the alterations induced by amiodarone was a mixture of both. There was no correlation, therefore, between the induced cellular chemical contents and morphologic changes. Despite the physicochemical similarity of the amphiphilic drugs (all have cationic and lipophilic moieties), the chemical responses they induced were different. The results suggest that amphiphilic drugs alter processes involving saccharides as well as those of phospholipid metabolism. The origin of the saccharide moieties associated with the induced changes in monosaccharide contents is not known. Increased content of phosphatidylinositol, mannose, and glycosyl residues is consistent with the suggestion that amphiphilic drugs may cause an increase in membrane anchor synthesis. The inhibition of lysosomal enzyme activities responsible for the degradation of phospholipid and other anchors may also account for the observed increase in monosaccharides and phosphatidylinositol content.
在研究与细胞内药物储存相关的细胞变化时，我们用各种两亲性药物孵育培养的兔主动脉肌细胞。二丁胺、氯喹和地昔帕明均增加了鼠李糖、阿拉伯糖、甘露糖、葡萄糖和总糖的细胞含量；这些药物还提高了所有种类的总磷脂和各磷脂的含量。胺碘酮没有改变总糖含量，但增加了总磷脂。相比之下，替洛隆降低了总糖含量，但磷脂含量未变。所有测试药物均降低了木糖含量。通过光学显微镜观察，二丁胺、氯喹和替洛隆诱导形成清晰的细胞质空泡；地昔帕明诱导形成致密的细胞质颗粒；胺碘酮则诱导了两种细胞质变化。通过电子显微镜观察，二丁胺诱导的细胞改变内容物主要是电子透亮的；地昔帕明诱导的改变内容物主要是同心层状体/絮状电子致密结构；胺碘酮诱导的改变内容物则是两者的混合物。因此，诱导的细胞化学含量与形态学变化之间没有相关性。尽管两亲性药物在物理化学性质上相似（均具有阳离子和亲脂性部分），但它们诱导的化学反应却不同。结果表明，两亲性药物会改变涉及糖类以及磷脂代谢的过程。与单糖含量诱导变化相关的糖部分的来源尚不清楚。磷脂酰肌醇、甘露糖和糖基残基含量的增加与两亲性药物可能导致膜锚合成增加的观点一致。负责磷脂和其他锚降解的溶酶体酶活性的抑制也可能解释观察到的单糖和磷脂酰肌醇含量的增加。
