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J Biol Chem, Vol. 274, Issue 37, 26051-26056, September 10, 1999
From the Bernhard Nocht Institute for Tropical Medicine,
Bernhard-Nocht-Strasse 74, 20359 Hamburg, Germany
To obtain insight into the mechanism of
metronidazole resistance in the protozoan parasite Entamoeba
histolytica, amoeba trophozoites were selected in
vitro by stepwise exposures to increasing amounts of
metronidazole, starting with sublethal doses of 4 µM.
Subsequently, amoebae made resistant were able to continuously multiply
in the presence of a 40 µM concentration of the drug. In
contrast to mechanisms of metronidazole resistance in other protozoan
parasites, resistant amoebae did not substantially down-regulate
pyruvate:ferredoxin oxidoreductase or up-regulate P-glycoproteins, but
exhibited increased expression of iron-containing superoxide dismutase
(Fe-SOD) and peroxiredoxin and decreased expression of flavin reductase
and ferredoxin 1. Episomal transfection and overexpression of the various antioxidant enzymes revealed significant reduction in susceptibility to metronidazole only in those cells overexpressing Fe-SOD. Reduction was highest in transfected cells simultaneously overexpressing Fe-SOD and peroxiredoxin. Although induced
overexpression of Fe-SOD did not confer metronidazole resistance to the
extent found in drug-selected cells, transfected cells quickly adapted to constant exposures of otherwise lethal metronidazole concentrations. Moreover, metronidazole selection of transfected amoebae favored retention of the Fe-SOD-containing plasmid. These results strongly suggest that peroxiredoxin and, in particular, Fe-SOD together with
ferredoxin 1 are important components involved in the mechanism of
metronidazole resistance in E. histolytica.
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