Differential effects of oltipraz and its oxy-analogue on the viability of Schistosoma mansoni and the activity of glutathione S-transferase.
Adult worms of Schistosoma mansoni recovered from mice treated with oltipraz (OPZ) showed a significant diminution in their ability to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) to formazan, a measure of parasite viability. Incubation of glutathione S-transferase (GST) from S. mansoni with OPZ resulted in a time- and concentration-dependent inhibition of enzyme activity. RP 36,642 (an inactive oxy-derivative of OPZ) had a minimal effect on the viability of the worms and no effect on GST activity. The structural integrity of OPZ, particularly the thione sulphur, appears to be necessary for expression of the antischistosomal effects of the drug. OPZ-induced inhibition of GST was non-competitive with either reduced glutathione (GSH) or 1-chloro-2,4-dinitrobenzene (CDNB), indicating that the drug is not a substrate for GST-catalysed conjugation reactions. In addition, the inhibition of GST could not be reversed by dialysis or repurification of the enzyme via a GSH-agarose affinity column. The effects of OPZ on GST activity could render the parasite vulnerable to damage by host-derived reactive oxygen species and aldehydic products of lipid peroxidation. The effects of OPZ on GST activity may play a role in the antischistosomal action of OPZ.
Nare
B
B
Institute of Parasitology, McGill University, Macdonald College, St. Anne de Bellevue, Quebec, Canada.
Smith
J M
JM
Prichard
R K
RK
D000818:Animals; D004137:Dinitrochlorobenzene / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D007700:Kinetics; D008297:Male; D051379:Mice; D011719:Pyrazines / Q000627:therapeutic use*; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D012555:Schistosomiasis mansoni / Q000188:drug therapy*; D012556:Schistosomicides / Q000627:therapeutic use*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013871:Thiones; D013876:Thiophenes
D004137:Dinitrochlorobenzene; D011719:Pyrazines; D012556:Schistosomicides; D013778:Tetrazolium Salts; D013844:Thiazoles; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D005982:Glutathione Transferase; C022616:thiazolyl blue; D005978:Glutathione