Elsevier

Toxicology Letters

Volume 73, Issue 3, September 1994, Pages 201-208
Toxicology Letters

Leupeptin and E-64, inhibitors of cysteine proteinases, prevent gentamicin-induced lysosomal phospholipidosis in cultured rat fibroblasts

https://doi.org/10.1016/0378-4274(94)90059-0Get rights and content

Abstract

Aminoglycoside antibiotics, such as gentamicin, cause an early lysosomal phospholipidosis in the renal cortex, which is considered as a key event in the onset of acute tubular necrosis induced by these drugs. In a model of primary cultures of embryonic rat fibroblasts which develop typical lysosomal phospholipidosis when incubated with gentamicin (decrease of sphingomyelinase activity; increase in total cells lipid phosphorus; appearance of so-called ‘myeloid bodies’ in lysosomes), we observed a protective effect exerted by inhibitors of cysteine proteinases (leupeptin, E-64) against this alteration on the basis of both biochemical and morphological criteria. Actually leupeptin and E-64 caused a marked stimulation of sphingomyelinase activity both in control and in gentamicin-treated cells, which we suggest to be the cause of protection.

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    • Cocaine induces a mixed lysosomal lipidosis in cultured fibroblasts, by inactivation of acid sphingomyelinase and inhibition of phospholipase A1

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      The rapid recovery of acid sphingomyelinase upon cocaine withdrawal points to a fast turnover of acid sphingomyelinase in the cells. Interestingly, in gentamicin-induced lipid storage disorders, sphingomyelinase activity was also decreased and inhibitors of cysteine proteinases exerted a protective effect (Montenez et al., 1994a,b). Similarly, cell treatment with the antidepressant, desipramine, induced a loss of sphingomyelinase activity that was prevented by leupeptin (Hurwitz et al., 1994).

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