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Myeloperoxidase-generated phenothiazine cation radicals inactivate Trypanosoma cruzi dihydrolipoamide dehydrogenase
Gutiérrez-Correa, J; Stoppani, A. O. M.
Afiliação
  • Gutiérrez-Correa, J; University of Buenos Aires. School of Medicine. Bioenergetics Research Centre. Argentina
  • Stoppani, A. O. M; University of Buenos Aires. School of Medicine. Bioenergetics Research Centre. Argentina
Rev. argent. microbiol ; 34(2): 83-94, abr.-jun. 2002.
Artigo em Inglês | BINACIS | ID: bin-6776
Biblioteca responsável: BR1.1
ABSTRACT
Peroxidase/H2O2/phenothiazine systems irreversibly inhibit Trypanosoma cruzi dihydrolipoamide dehydrogenase (LADH). Inactivation of the parasite enzyme depended on (a) phenothiazine structure; (b) peroxidase nature; (c) incubation time and (d) the presence of a cation radical scavenger. With the myeloperoxidase/H2O2/system, promazine, trimeprazine, thioridazine, promethiazine, prochlorperazine, chlorpromazine and perphenazine were the most effective derivatives out of twelve phenothiazines studied. An electronegative substituent at position 2 of the phenothiazine ring such as Cl, or trifluoromethyl, propionyl and nitrile groups decreased or nullified phenothiazine activity. Myeloperoxidase/H2O2/, horseradish peroxidase/H2O2/, and myoglobin/H2O2/systems activated phenothiazines producing the corresponding cation radicals, myeloperoxidase being the most selective one with respect to phenothiazine structure. The myoglobin/H2O2/system activated phenothiazines that were scarcely active or inactivate with the MPO/H2O2/system, such as the trifluoromethyl derivatives. Production of phenothiazine cation radicals was demonstrated by optical spectroscopy. Phenothiazine cation radical stability depended on their structure as illustrated by promazine and thioridazine. Thiol compounds (GSH, N-acetyl-cysteine and penicillamine), aromatic aminoacids (L-tyrosine, L-tryptophan, and the corresponding peptides) and ascorbate scavenged phenothiazine cation radicals, thus preventing LADH inactivation. Comparison of the summarized phenothiazine effects with those of phenothiazines on T. cruzi suggest the role of cation radicals in phenothiazines chemotherapeutic actions.(AU)
Assuntos
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Coleções: Bases de dados nacionais / Argentina Contexto em Saúde: Doenças Negligenciadas Problema de saúde: Doença de Chagas / Doenças Negligenciadas Base de dados: BINACIS Assunto principal: Fenotiazinas / Tripanossomicidas / Trypanosoma cruzi / Cátions / Proteínas de Protozoários / Peroxidase / Inibidores Enzimáticos / Di-Hidrolipoamida Desidrogenase Limite: Animais / Humanos Idioma: Inglês Revista: Rev. argent. microbiol Ano de publicação: 2002 Tipo de documento: Artigo Instituição/País de afiliação: University of Buenos Aires/Argentina
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Coleções: Bases de dados nacionais / Argentina Contexto em Saúde: Doenças Negligenciadas Problema de saúde: Doença de Chagas / Doenças Negligenciadas Base de dados: BINACIS Assunto principal: Fenotiazinas / Tripanossomicidas / Trypanosoma cruzi / Cátions / Proteínas de Protozoários / Peroxidase / Inibidores Enzimáticos / Di-Hidrolipoamida Desidrogenase Limite: Animais / Humanos Idioma: Inglês Revista: Rev. argent. microbiol Ano de publicação: 2002 Tipo de documento: Artigo Instituição/País de afiliação: University of Buenos Aires/Argentina
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