The substituted benzimidazole omeprazole, used for the treatment of human peptic ulcer disease, inhibits the growth of the metronidazole-resistant bovine pathogen Tritrichomonas foetus in vitro (MIC at which the growth of parasite cultures is inhibited by 50%, 22 microg/ml [63 microM]). The antitrichomonad activity appears to be due to the inhibition of pyruvate decarboxylase (PDC), which is the key enzyme responsible for ethanol production and which is strongly upregulated in metronidazole-resistant trichomonads. PDC was purified to homogeneity from the cytosol of metronidazole-resistant strain. The tetrameric enzyme of 60-kDa subunits is inhibited by omeprazole (50% inhibitory concentration, 16 microg/ml). Metronidazole-susceptible T. foetus, which expresses very little PDC, is only slightly affected. Omeprazole has the same inhibitory effect on T. foetus cells grown under iron-limited conditions. Similarly to metronidazole-resistant cells, T. foetus cells grown under iron-limited conditions have nonfunctional hydrogenosomal metabolism and rely on cytosolic PDC-mediated ethanol fermentation.

• MeSH
• Antitrichomonal Agents pharmacology   MeSH
• Iron Deficiencies * MeSH
• Electrophoresis, Polyacrylamide Gel MeSH
• Enzyme Inhibitors pharmacology   MeSH
• Kinetics MeSH
• Drug Resistance MeSH
• Metronidazole pharmacology   MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• Omeprazole pharmacology   MeSH
• Pyruvate Decarboxylase drug effects   MeSH
• Tritrichomonas foetus drug effects   MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antitrichomonal Agents MeSH
• Enzyme Inhibitors MeSH
• Metronidazole MeSH
• Omeprazole MeSH
• Pyruvate Decarboxylase MeSH

The assumption that the pyruvate decarboxylase activity of Saccharomyces carlsbergensis is the main limiting factor determining the formation rate and the total amount of d(--)-l-hydroxy-l-phenyl-propanone (phenylacetylcarbinol, PAC) produced was not confirmed. An increase of about 30% of the total amount of the PAC produced was obtained when 8.5% sodium pyruvate was gradually added. The total PAC production is probably influenced both by the pyruvate decarboxylase activity and the pyruvate concentration in the cells, the latter being actually the determining rate-limiting factor.

• MeSH
• Acetone analogs & derivatives   biosynthesis   MeSH
• Carboxy-Lyases metabolism   MeSH
• Kinetics MeSH
• Pyruvic Acid MeSH
• Pyruvate Decarboxylase metabolism   MeSH
• Pyruvates metabolism   pharmacology   MeSH
• Saccharomyces metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 1-hydroxy-1-phenyl-2-propanone MeSH Browser
• Acetone MeSH
• Carboxy-Lyases MeSH
• Pyruvic Acid MeSH
• Pyruvate Decarboxylase MeSH
• Pyruvates MeSH