title: Mechanisms of inactivation of Schistosoma mansoni and mammalian glutathione S-transferase activity by the antischistosomal drug oltipraz.
abstract: Glutathione S-transferase (GST) purified from Schistosoma mansoni or human placenta was inhibited by the antischistosomal drug oltipraz (OPZ) in a time- and concentration-dependent manner. Inhibition of placenta GST was complete at a low concentration of drug, whereas that of parasite GST was incomplete and relatively high amounts of OPZ were needed to reach 50% inhibition. Complete reactivation of GST from placenta was achieved with dithiothreitol (DTT) and other sulfhydryl-containing compounds, while the inactivation of parasite GST was irreversible. The oxy-derivative of OPZ (RP 36,642), in which the thione sulfur is replaced with oxygen, did not inhibit GST activity. There were no differences between OPZ and RP 36,642 in their patterns of binding to the hydrophobic non-substrate site of GST. GST from the placenta incorporated much higher levels of [14C]N-ethylmaleimide compared to schistosome GST. The incorporation of [14C]N-ethylmaleimide by GST was inhibited by OPZ but not by RP 36,642. Yeast and S. mansoni hexokinases were similarly inhibited by OPZ but not by RP 36,642. Both hexokinase preparations recovered their activity following incubation with DTT. These data suggest that the inactivation of these enzymes by OPZ is a result of its interaction with their SH groups. Thus, the antischistosomal activity of OPZ may be accounted for by its interaction with the SH groups of macromolecules in general.
authors.affiliation: Institute of Parasitology, Macdonald College, McGill University, Quebec, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Nare
authors.forename: J M
authors.initials: JM
authors.lastname: Smith
authors.forename: R K
authors.initials: RK
authors.lastname: Prichard
mesh_terms: D000818:Animals; D001665:Binding Sites; D004229:Dithiothreitol / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005033:Ethylmaleimide / Q000494:pharmacology; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D006801:Humans; D011719:Pyrazines / Q000494:pharmacology* / Q000633:toxicity; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology; D012556:Schistosomicides / Q000494:pharmacology* / Q000633:toxicity; D013871:Thiones; D013876:Thiophenes
chemical_list: D011719:Pyrazines; D012556:Schistosomicides; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D005982:Glutathione Transferase; D005033:Ethylmaleimide; D004229:Dithiothreitol