Changes in saccharide and phospholipid content associated with drug storage in cultured rabbit aorta muscle cells.
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.
Ruben
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Department of Pathology, G.D. Searle & Company, Skokie, Illinois.
Anderson
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Kacew
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D000588:Amines / Q000494:pharmacology*; D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001011:Aorta / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D007700:Kinetics; D008854:Microscopy, Electron; D009005:Monosaccharides / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010743:Phospholipids / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D013994:Tilorone / Q000494:pharmacology
D000588:Amines; D000889:Anti-Arrhythmia Agents; D005029:Ethylenediamines; D009005:Monosaccharides; D010743:Phospholipids; D010880:Piperidines; C005798:N,N,N',N'-tetramethylethylenediamine; C030153:disobutamide; D002738:Chloroquine; D000638:Amiodarone; D013994:Tilorone; D003891:Desipramine