Succinylacetone Oxidation by Oxygen/Peroxynitrite: A Possible Source of Reactive Intermediates in Hereditary Tyrosinemia Type I

详细信息    查看全文

• 作者：Leandro O. Royer ; Fernanda S. Knudsen ; Marcone A. de Oliveira ; Marina F. M. Tavares ; and Etelvino J. H. Bechara
• 刊名：Chemical Research in Toxicology
• 出版年：2004
• 出版时间：May 2004
• 年：2004
• 卷：17
• 期：5
• 页码：598 - 604
• 全文大小：133K
• 年卷期：v.17,no.5(May 2004)
• ISSN：1520-5010

文摘

Hereditary tyrosinemia type I (HT1) is an inborn metabolic error characterized by hepatorenaldysfunction. Affected patients excrete large quantities of succinylacetone (SA), a tyrosinecatabolite believed to be involved in the pathogenesis of HT1. A growing body of evidence relatesthe oxidative stress observed in metabolic disorders to free radicals generated from accumulatedmetabolites. In this context, oxidation of SA by peroxynitrite or cytochrome c yielding reactiveintermediates and products was investigated here. Both peroxynitrite and cytochrome c wereable to initiate oxygen consumption by SA, which was followed by polarimetric and chemiluminescence measurements. The light emission arises from triplet carbonyls formed by thethermolysis of dioxetane intermediates, as indicated by energy transfer experiments. EPR spin-trapping studies with 2-methyl-2-nitrosopropane revealed the intermediacy of two differentcarbon-centered radicals, one of them originating from cleavage of the triplet carbonyl product.The pH profiles obtained by oxygen consumption, chemiluminescence, and stopped-flowspectrophotometry point to the peroxynitrite anion as the initiator of SA aerobic oxidation.Overstoichiometric formation of organic acids based on added peroxynitrite confirms theoccurrence of an oxygen-dependent chain reaction, here proposed to be initiated by one electronabstraction from the enolic form of SA. The results obtained may help shed light on the roleof both SA and oxidative stress in the pathogenesis of HT1.