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(Received for publication, November 21, 1996, and in revised form, March 25, 1997)
From the Departments of Medicine and Cell Biology, Duke University
Medical Center, Durham, North Carolina 27710
Sphingomyelin hydrolysis through the activation
of sphingomyelinases has become a potentially important signaling
pathway with the product ceramide implicated in the regulation of cell growth, differentiation, apoptosis, and inflammatory responses. However, little is known about the regulation of sphingomyelinases. In
this study, we show that the magnesium-dependent, neutral
pH-optimum and membrane-associated sphingomyelinase (N-SMase) is
inhibited, in a dose-dependent manner, by glutathione (GSH)
at physiological concentrations with a greater than 95% inhibition
observed at 5 mM GSH. The inhibitory effect of GSH
was reproduced by
Volume 272, Number 26,
Issue of June 27, 1997
pp. 16281-16287
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
-glutamyl-cysteine, but not the cysteinyl-glycine
fragment of GSH. The S-modified GSH analogs were as
effective as GSH in inhibiting the N-SMase. On the other hand, neither
dithiothreitol nor 
-mercaptoethanol had any effect on the N-SMase,
suggesting that the sulfhydryl in GSH is not required for inhibition of
N-SMase. GSH had no effect on the acid pH-optimum SMase, whereas
dithiothreitol inhibited the acid SMase. These results suggest that in
cells the N-SMase is inactive in the presence of physiological
concentrations of GSH (1-20 mM). Finally, treatment of
cultured Molt-4 cells with the GSH synthesis inhibitor,
L-buthionine-(SR)-sulfoximine, resulted in a
time-dependent depletion of GSH, accompanied by an
increased hydrolysis of sphingomyelin and production of ceramide. Since GSH depletion is observed in a variety of cells in the process of
cellular injury and apoptosis, these studies suggest that depletion of
GSH may be an important mechanism in activation of N-SMase. This
mechanism may therefore bring together the fields of oxidative stress
and signaling through products of sphingomyelin hydrolysis.
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