The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts.

The effect of the tricyclic antidepressant desipramine on the processing of lysosomal sphingomyelinase (EC 3.1.4.12) was investigated by pulse-chase studies on [35S]methionine labeled cultured human skin fibroblasts. Desipramine induced rapid intracellular degradation of mature acid sphingomyelinase when added to the cells in the micromolar range, concomitantly abolishing the enzyme activity. Pulse chase labeling revealed the disappearance of mature enzyme forms when fibroblasts were treated with 25 microM desipramine. Incubation of cells with 25 microM leupeptin, an inhibitor of thiol proteases, 24 h prior to desipramine intoxication prevented this drug-induced effect. From these results we conclude that desipramine and possibly also similarly acting tricyclic antidepressants induce proteolytic degradation of acid sphingomyelinase.