In vitro and in vivo ultrastructural changes induced by macrolide antibiotic LY281389
High doses of LY281389 (9-N-(n-propyl)-erythromycylamine) cause cytoplasmic vacuolar changes in striated and smooth muscle characteristic of drug-induced phospholipidosis. This study characterized phospholipidosis in striated and smooth muscle of rats and dogs, compared in vivo observations with tho...
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Published in | Fundamental and applied toxicology Vol. 32; no. 2; pp. 205 - 216 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Boston, MA
Academic Press
01.08.1996
San Diego, CA New York, NY |
Subjects | |
Online Access | Get full text |
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Summary: | High doses of LY281389 (9-N-(n-propyl)-erythromycylamine) cause cytoplasmic vacuolar changes in striated and smooth muscle characteristic of drug-induced phospholipidosis. This study characterized phospholipidosis in striated and smooth muscle of rats and dogs, compared in vivo observations with those in a cultured rat myoblast model, and attempted to confirm the lysosomal origin of the drug-induced vacuoles. Standard transmission electron microscopy and acid phosphatase cytochemistry techniques were used to evaluate ultrastructural changes in vivo and in vitro. Rats and dogs exposed to LY281389 had a time- and dose-related increase in number and size of vacuoles containing concentric lamellar figures in cardiac and skeletal muscle. Cytochemical staining of dog stomach smooth muscle for acid phosphatase, a lysosomal enzyme, stained the periphery of vacuoles that contained concentric lamellar figures. Cultured rat L6 myoblast cells were exposed to 0.25 mg LY281389/ml for 2.5, 5, 10, 20, 30, or 90 min and 2, 6, 12, 24, or 48 hr. Cell cultures exposed for 2 hr had several predominantly large, clear, membrane-bound vacuoles, and at 6 and 12 hr there were greater numbers of large vacuoles that contained increased amounts of membranous figures. Following 24- or 48-hr exposures, vacuoles occupied most of the cytoplasmic volume, and were engorged predominantly with amorphous or granular material. These findings indicate that LY281389 can induce similar phospholipidosis-like vacuolar changes in rat and dog muscle and in a cultured rat muscle cell line. Further, positive acid phosphatase staining of drug-induced vacuolar structures, in conjunction with standard transmission electron microscopy techniques, strongly suggests that vacuoles seen in vitro and in vivo are lysosomal in origin. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0272-0590 1095-6832 |
DOI: | 10.1006/faat.1996.0123 |