Trypanosoma cruzi dihydrolipoamide dehydrogenase as target for phenothiazine cationic radicals. Effect of antioxidants.

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Gutierrez-Correa J

Trypanosoma cruzi dihydrolipoamide dehydrogenase as target for phenothiazine cationic radicals. Effect of antioxidants.

Curr Drug Targets. 2006 Sep;7(9):1155-79.

PubMed ID

17017892 [ View in PubMed

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Abstract

Myeloperoxidase (MPO), myoglobin (Mb) and horseradish peroxidase (HRP), catalyzed the generation of radical-cations by one-electron oxidation of phenothiazines (PTZ). The transient formation of these radicals (PTZ+.) was confirmed by ESR and optical spectroscopy. These species are reactive towards Trypanosoma cruzi LADH (T. cruzi LADH), T. cruzi trypanothione reductase (T. cruzi TR) and possibly other macromolecule targets. Both T. cruzi enzymes were irreversibly inactivated. T. cruzi LADH inactivation depended on: a) PTZ structure, peroxidase nature and the rate production of PTZ+. radical cations; b) incubation time; c) the presence of an antioxidant that intercepts free radicals. The production of PTZ+. radical cations, which is essential for T. cruzi LADH inactivation, is correlated with the electron donor ability of the substrates, as qualified by the Hammett sigmapara constant for the subtituent in the 2-position of the PTZ. Promazine (PZ), trimeprazine (TMPZ) and thioridazine (TRDZ) were the most effective inactivating agents, whereas trifluophenothiazines with CF3 group at 2-position (Trifluoperazine (TFP), fluphenazine (FFZ) and trifluopromazine (TFPZ)), and propericyazine (PCYZ) with CN group at 2-position, were much less active or inactive, all in close agreement with their higher or lowest electron donor ability, respectively. Comparison of inactivation values for T. cruzi LADH and mammalian heart LADH demonstrated a greater sensitivity of T. cruzi LADH to various PTZ studied. Thiol compounds, tyrosine, dopa, tryptophan, NADH, ascorbate and trolox prevented T. cruzi LADH inactivation by the peroxidase/H2O2 systems in agreement with their ability to suppress PTZ+. radical cations. The role of these radicals as enzyme inhibitors, or as generators of secondary free radicals and metabolite depletors may contribute to explain the trypanocidal effect as well as other chemotherapeutic actions of PTZ.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
NADH	Dihydrolipoyl dehydrogenase, mitochondrial	Protein	Humans	Unknown	Not Available	Details