Succinylacetone Oxidation by Oxygen/Peroxynitrite: A Possible Source of Reactive Intermediates in Hereditary Tyrosinemia Type I
| Autor: | Fernanda da Silva Knudsen, Leandro O. Royer, Marina Franco Maggi Tavares, Etelvino J. H. Bechara, Marcone Augusto Leal de Oliveira |
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| Rok vydání: | 2004 |
| Předmět: |
Free Radicals
Reactive intermediate Catabolite repression chemistry.chemical_element Toxicology Oxygen Phosphates Hemoglobins chemistry.chemical_compound Oxygen Consumption Peroxynitrous Acid Humans Tyrosine Tyrosinemias Spectrum Analysis Electrophoresis Capillary Hydrogen Peroxide General Medicine Hydrogen-Ion Concentration Heptanoates Hereditary tyrosinemia Oxidative Stress chemistry Succinylacetone Biochemistry Luminescent Measurements Cytochromes Oxidation-Reduction Peroxynitrite |
| Zdroj: | Chemical Research in Toxicology. 17:598-604 |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/tx0342520 |
| Popis: | Hereditary tyrosinemia type I (HT1) is an inborn metabolic error characterized by hepatorenal dysfunction. Affected patients excrete large quantities of succinylacetone (SA), a tyrosine catabolite believed to be involved in the pathogenesis of HT1. A growing body of evidence relates the oxidative stress observed in metabolic disorders to free radicals generated from accumulated metabolites. In this context, oxidation of SA by peroxynitrite or cytochrome c yielding reactive intermediates and products was investigated here. Both peroxynitrite and cytochrome c were able to initiate oxygen consumption by SA, which was followed by polarimetric and chemiluminescence measurements. The light emission arises from triplet carbonyls formed by the thermolysis of dioxetane intermediates, as indicated by energy transfer experiments. EPR spin-trapping studies with 2-methyl-2-nitrosopropane revealed the intermediacy of two different carbon-centered radicals, one of them originating from cleavage of the triplet carbonyl product. The pH profiles obtained by oxygen consumption, chemiluminescence, and stopped-flow spectrophotometry point to the peroxynitrite anion as the initiator of SA aerobic oxidation. Overstoichiometric formation of organic acids based on added peroxynitrite confirms the occurrence of an oxygen-dependent chain reaction, here proposed to be initiated by one electron abstraction from the enolic form of SA. The results obtained may help shed light on the role of both SA and oxidative stress in the pathogenesis of HT1. |
| Databáze: | OpenAIRE |
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