Glutathione redox state, lipid peroxide levels, and activities of glutathione enzymes in oltipraz-treated adult Schistosoma mansoni.
A decrease in reduced glutathione (GSH) levels in adult Schistosoma mansoni exposed in vitro to the antischistosomal drug oltipraz (OPZ) (20-60 nM) was accompanied by a significant increase in oxidized glutathione (GSSG) levels. The total glutathione (GSH + GSSG) levels also diminished in drug-treated parasites. The activities of the parasite glutathione peroxidase (GPO), utilizing cumene hydroperoxide as a substrate, and glutathione S-transferase (GST), measured 18 hr after in vitro incubation with the drug, were elevated significantly, but there were no significant alterations in the activities of the GPO, utilizing H2O2, or glutathione reductase (GR). Drug-treated worms showed increased lipid peroxidation. In vivo, the proportion of the worms recovered from infected mice given OPZ (100 mg/kg body wt) gradually declined with time, to about 30% of that recovered from infected untreated control mice by day 14 after drug administration, and consisted predominantly of male worms. Accompanying this significant decline in the proportion of worms recovered were significant decreases in the activities of the enzymes GR and GST in drug-exposed worms. On the other hand, a slight initial increase in the GPO activity with cumene hydroperoxide was followed by a return to control values, and the GPO activity with H2O2 was decreased only slightly with time. Interestingly, the 4-hydroxyalk-2-enal aldehydes, known products of lipid peroxidation, inhibited the GST reaction with 1-chloro-2,4-dinitrobenzene (CDNB). The OPZ-induced changes in S. mansoni could increase parasite susceptibility to oxidative attack by host phagocytes, and are probably linked with the antischistosomal action of the drug in vivo.
Mkoji
G M
GM
Institute of Parasitology, Macdonald College, McGill University, Ste-Anne de Bellevue, Quebec, Canada.
Smith
J M
JM
Prichard
R K
RK
D000818:Animals; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism*; D008054:Lipid Peroxides / Q000096:biosynthesis*; D051379:Mice; D010084:Oxidation-Reduction; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology; D012555:Schistosomiasis mansoni / Q000188:drug therapy / Q000469:parasitology; D012556:Schistosomicides / Q000494:pharmacology* / Q000627:therapeutic use; D013871:Thiones; D013876:Thiophenes
D008054:Lipid Peroxides; D011719:Pyrazines; D012556:Schistosomicides; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005978:Glutathione