ENDOTHALL THIOANHYDRIDE INHIBITS PROTEIN PHOSPHATASE-1 AND PHOSPHATASE-2A IN-VIVO

The objective of this study was to relate the toxicity of several cant haridin-derivative pesticides with their abilities to inhibit protein phosphatases-1 (PP1) and -2A (PP2A). Cantharidin (CA), endothall, and endothall thioanhydride (ETA) inhibited the activity of PP1 and PP2A, and the potency sequence was CA > endothall > ETA in vitro. We determi ned the inhibitory potency of these pesticides on hepatic protein phos phatases by administration of the toxins into the portal vein of rats. The potency sequence of ETA > CA > endothall was established for the inhibition of PP1 and PP2A in vivo and shows close correlation with th e sequence of relative toxicity. ETA predominantly targets PP1 for inh ibition in liver, as revealed by assays specific for PP1 or PP2A. Stud ies using 3T3 fibroblasts showed that only ETA, but not CA or endothal l, induced marked morphological changes. These effects included cell r ounding and detachment as well as extensive reorganization of actin fi laments and are characteristic for the cell-permeable phosphatase-inhi bitory toxins. It is suggested that the in vivo effectiveness is relat ed to enhanced uptake of ETA, because this is permeable across the pla smalemma.