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Id: lil-331800
Autor: Gutiérrez-Correa, J; Stoppani, A. O. M.
Título: Myeloperoxidase-generated phenothiazine cation radicals inactivate Trypanosoma cruzi dihydrolipoamide dehydrogenase
Fonte: Rev. argent. microbiol;34(2):83-94, abr.-jun. 2002.
Idioma: en.
Resumo: 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.
Descritores: Cátions
Di-Hidrolipoamida Desidrogenase
Inibidores Enzimáticos/farmacologia
Peroxidase
Fenotiazinas
Proteínas de Protozoários/antagonistas & inibidores
Tripanossomicidas
Trypanosoma cruzi
-Ácido Ascórbico/farmacologia
Aminoácidos Aromáticos/farmacologia
Depuradores de Radicais Livres
Radicais Livres
Peroxidase
Peróxido de Hidrogênio/metabolismo
Proteínas Recombinantes de Fusão/antagonistas & inibidores
Relação Estrutura-Atividade
Compostos de Sulfidrila
Trypanosoma cruzi
Limites: Animais
Humanos
Tipo de Publ: Estudo Comparativo
Research Support, Non-U.S. Gov't
Responsável: BR1.1 - BIREME



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