POSSIBLE PROTEIN PHOSPHATASE INHIBITION BY BIS(HYDROXYETHYL)SULFIDE, A HYDROLYSIS PRODUCT OF MUSTARD GAS

Recently, the natural vesicant cantharidin was shown to bind exclusive ly to and inhibit protein phosphatase 2A (PP2A) in mouse tissue extrac ts (Li and Casida (1992) Proc. Natl. Acad. Sci. USA 89, 11867-11870). To explore the generality of this effect in vesicant action, we measur ed the protein serine/threonine phosphatase activity in mouse liver cy tosol (in the form of the okadaic acid inhibitable increment of p-nitr ophenyl phosphate (p-NPP) phosphatase activity) in the presence of aqu eous sulfur mustard or its hydrolysis product, bis(hydroxyethyl)sulfid e (TDG). Sulfur mustard inhibited p-NPP hydrolysis. However, inhibitio n correlated with the time elapsed between thawing and the addition of mustard to the enzyme preparation, not with concentration. TDG exhibi ted a direct, concentration-related inhibition of p-NPP hydrolysis bet ween 30 and 300 mu M. We conclude that sulfur mustard also has an inhi bitory effect on protein serine/threonine phosphatases. However, the i nhibition is an effect of its non-alkykating hydrolysis product TDG, n ot of sulfur mustard itself.