Sodium stibogluconate (Pentostam) inhibition of glucose catabolism via the glycolytic pathway, and fatty acid beta-oxidation in Leishmania mexicana amastigotes.
The biochemical mechanism of action of antimony (Sb) in pentavalent form complexed to gluconic acid (sodium stibogluconate)--the drug of choice for the leishmaniases--has been only slightly investigated. We recently reported that, in stibogluconate-exposed Leishmania mexicana amastigotes, there is a dose-dependent decrease in the ATP/ADP ratio [Berman et al., Antimicrob. Agents Chemother. 27, 916 (1985)]. To investigate mechanisms by which ADP phosphorylation to ATP might be inhibited, stibogluconate-exposed amastigotes were incubated with [14C]glucose, fatty acid, or acetate, and 14CO2 production was determined. In organisms exposed to 500 micrograms Sb/ml, formation of 14CO2 from [6-14C]glucose and [1-14C]palmitate was inhibited 69 and 67% respectively. In comparison, formation of 14CO2 from [1-14C]glucose and [2-14C]acetate was inhibited less than 15%. These results suggest that glucose catabolism via glycolytic enzymes and fatty acid beta-oxidation, but not glucose metabolism via the hexosemonophosphate shunt or the citric acid cycle, is specifically inhibited in stibogluconate-exposed Leishmania mexicana amastigotes. Inhibition of these pathways suggests a mechanism for the inhibition of ADP phosphorylation previously reported.
D000085:Acetates / Q000378:metabolism; D000818:Animals; D000967:Antimony Sodium Gluconate / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D005227:Fatty Acids / Q000378:metabolism*; D005942:Gluconates / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects*; D007700:Kinetics; D007894:Leishmania mexicana / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000378:metabolism
D000085:Acetates; D002250:Carbon Radioisotopes; D005227:Fatty Acids; D005942:Gluconates; D010169:Palmitic Acids; D019308:Palmitic Acid; D005947:Glucose; D000967:Antimony Sodium Gluconate