Susceptibility of an emetine-resistant mutant of Entamoeba histolytica to multiple drugs and to channel blockers.
Previously a cloned emetine-resistant mutant of the protozoal parasite Entamoeba histolytica was shown to overexpress a gene for an ameba homolog of the mammalian P-glycoprotein, a plasma membrane pump that removes hydrophobic drugs from multidrug-resistant tumor cells. Three sets of experiments were performed to better characterize the multidrug-resistant phenotype of the emetine-resistant amebae. First, the emetine resistance of the mutant amebae was reversed by concentrations of calcium and sodium channel blockers effective in reversing drug resistance by multidrug-resistant tumor cells, but it was reversed only in the presence of very high concentrations of the tricyclic antidepressants. Second, the mutant amebae showed cross-resistance to antiamebic drugs used to treat luminal infection (iodoquinol and diloxanide) but were not cross-resistant to drugs used to treat invasive disease (chloroquine and metronidazole). Third, when amebae were loaded with radiolabeled emetine, the mutant parasites released the drug at approximately 1.6 times the rate of the wild-type organisms. We conclude that the emetine-resistant E. histolytica parasites have some but not all the features of the multidrug-resistant phenotype.
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D002999:Clone Cells / Q000378:metabolism / Q000502:physiology; D004351:Drug Resistance; D004640:Emetine / Q000493:pharmacokinetics / Q000494:pharmacology*; D004748:Entamoeba histolytica / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005663:Furans / Q000494:pharmacology; D004103:Iodoquinol / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects; D008795:Metronidazole / Q000494:pharmacology; D009154:Mutation; D010641:Phenotype
D000929:Antidepressive Agents, Tricyclic; D002121:Calcium Channel Blockers; D005663:Furans; D007473:Ion Channels; D008795:Metronidazole; D004103:Iodoquinol; D002738:Chloroquine; D004640:Emetine; C004932:diloxanide furoate