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Title: Schistosoma mansoni: glutathione S-transferase-catalyzed detoxication of dichlorvos.

Authors: O'Leary, K A; Tracy, J W

Published In Exp Parasitol, (1991 May)

Abstract: Dialyzed cytosol of adult Schistosoma mansoni worm pairs catalyzed the glutathione-dependent O-demethylation of dichlorvos (2,2-dichlorovinyl dimethylphosphate), the active form of the antischistosomal drug metrifonate, to form a thioether conjugate, S-methylglutathione, and desmethyl dichlorvos. The reaction rate was dependent on both time and protein concentration, and no product was formed when either dichlorvos or glutathione was omitted from the reaction mixture. Female worm cytosols were about 2.5-fold more active per milligram of protein that those of males. Partial purification of glutathione S-transferases from male worms by affinity chromatography on glutathione-agarose showed that the reaction could be catalyzed by a preparation containing the three major isoenzymes, but that the unbound fraction, which contains at least one additional form of the enzyme that is particularly active with epoxide substrates, was 16-fold more active toward dichlorvos than the bound fraction. S-Methylglutathione also was formed by S. mansoni worm pairs incubated in the presence but not in the absence of dichlorvos. Because GSH S-transferase-catalyzed metabolism of dichlorvos results in the formation of desmethyldichlorvos, which unlike the parent compound is not an effective acetylcholinesterase inhibitor, the reaction represents a pathway of detoxication in schistosomes. It is the first example of a clinically used schistosomicide shown to be detoxicated by a conjugation pathway. These results raise the possibility that dichlorvos detoxication by S. mansoni may help explain why this species is normally refractory to metrifonate.

PubMed ID: 2026213 Exiting the NIEHS site

MeSH Terms: Animals; Cytosol/enzymology; Dichlorvos/metabolism*; Dinitrochlorobenzene/metabolism; Epoxy Compounds/metabolism; Female; Glutathione Transferase/metabolism*; Glutathione/analogs & derivatives; Glutathione/metabolism; Inactivation, Metabolic; Kinetics; Male; Methylation; Nitrobenzenes/metabolism; Schistosoma mansoni/enzymology*

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