Effects of intermediary metabolites and electron transport inhibitors on action of chloroquine on Brugia pahangi and Onchocerca volvulus.
We examined the possibility that chloroquine is interfering with aerobic energy-generating processes in the adult filarial parasites, Brugia pahangi and Onchocerca volvulus. Using motility of these parasites as an assay of drug effect, we found that micromolar concentrations of chloroquine caused significant paralysis, but only in alkaline medium (pH 8.4). The addition of 12 mM glutamine or 10 mM albizziin to the medium completely antagonized drug-induced paralysis. In addition, in B. pahangi, all of the tricarboxylic acid cycle intermediates (10 mM) except citrate and pyruvate antagonized the effect of chloroquine on motility; in O. volvulus, oxaloacetate as well as glutamine inhibited the effect of the drug. The effect of chloroquine on both parasites was enhanced when it was used in combination with 10 microM acivicin, a glutamine antimetabolite. Here motility of B. pahangi was reduced significantly within 24-48 hr at acidic (6.8) neutral (7.4) and alkaline (8.4) pH. This effect was partially reversible by glutamine (12 mM). Motility of O. volvulus was reduced to near zero within 4 hr with this drug combination. Antimycin A and rotenone, both electron transport inhibitors, also synergized with chloroquine at any pH to produce paralysis in B. pahangi. The effects of the rotenone and chloroquine combination were reversed in the presence of 10 mM succinate. However, glutamine (12 mM) was unable to antagonize the effects of chloroquine plus antimycin A on the motility of B. pahangi. These findings suggest that chloroquine may be inhibiting aerobic energy metabolism in the filariae, possibly at the level of electron transport. Furthermore, since chloroquine is well-tolerated but only weakly filaricidal in vivo, the data indicate that use of this drug in combination with other inhibitors of aerobic energy metabolism may be a chemotherapeutically useful approach to the treatment of filariases.
VandeWaa
E A
EA
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
Williams
J F
JF
Geary
T G
TG
D000599:Amino Acids, Diamino / Q000494:pharmacology; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D002009:Brugia / Q000187:drug effects* / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D002952:Citric Acid Cycle; D004347:Drug Interactions; D004579:Electron Transport / Q000187:drug effects; D005849:Gerbillinae; D005973:Glutamine / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D009854:Onchocerca / Q000187:drug effects* / Q000502:physiology; D012402:Rotenone / Q000494:pharmacology
D000599:Amino Acids, Diamino; D007555:Isoxazoles; D012402:Rotenone; D005973:Glutamine; D000968:Antimycin A; D002738:Chloroquine; C006303:acivicin; C006440:albizziin