At this step it should be highlighted that the safety record of NTZ is excellent with little unwanted side effects. Consequently, uncoupling is rather considered as an unwanted side effect for a drug. Severe adverse effects appeared and for this reason dinitrophenol was banished from use 6. Actually, the first uncoupler (dinitrophenol) was used to promote weight loss 5. If this is not possible toxic effects are expected. The cell/animal aims to compensate the deterioration of yield by an increased respiratory activity and, when possible, it would simply result in an increase in energy expenditure.
The molecular explanation is that uncouplers increase the passive proton conductance of the mitochondrial inner membrane (chemiosmotic theory of Peter Mitchell). Two types of interferences might therefore be expected: either the OXPHOS is impaired by poisoning or the yield of conversion is deteriorated and this is how uncouplers act. In contrast with these enzymatic reactions, OXPHOS is not stoichiometric and therefore the actual number of ATP generated differs from the theoretical prediction and depends on the yield of conversion between substrate oxidation and ATP formation. Beside OXPHOS part of ATP is generated by substrate linked phosphorylation steps during glycolysis or TCA cycle. in most animals OXPHOS is the largest contributor to cellular energy metabolism. The main role for cellular respiration is the oxidative phosphorylation (OXPHOS) that regenerates continuously the ATP whose hydrolysis feeds the cellular energy requirements. The second type of interference proposed for NTZ refers to the uncoupling of cellular respiration. Therefore, indication for absence of a metabolic interference of the same nature in mammalian cells is lacking and effect through PFOR inhibition in target species remains uncertain. Another issue is the presence of the nitro group that was apparently required for inhibition of PFOR while derivatives without this nitro group showed similar anti parasitic activities 4. This TPP is also a cofactor for mammalian pyruvate dehydrogenase (PDH) and inhibition of mammalian PDH was not examined. This effect would rely on the similarity between NTZ and Thiamine pyrophosphate (TPP) a cofactor used by PFOR. This enzyme is essential for their anaerobic energy metabolism and is not found in mammals. A first proposal was that the therapeutic effect of NTZ relies on the specific properties of a metabolic enzyme found in the target species: the pyruvate ferredoxin oxidoreductase (PFOR) 3.
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