Mechanistic study of oxidative lesions in biomolecules by aminoacetone

Author(s)

Fernando Dutra

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2003-05-12

Examining board members

Etelvino Jose Henriques Bechara; Dulcineia Saes Parra Abdalla; Ohara Augusto; Rui Curi; Luiz Fernando da Silva Junior

• Advisor: Etelvino Jose Henriques Bechara

Abstract

Aminoacetone (AA) is a threonine and glycine catabolite long known to accumulate in cri-du-chat and threoninemia syndromes and, more recent1y, implicated as a contributing source of methylglyoxal (MG) in diabetes mellitus. AcetylCoA overproduction in diabetes also leads to AA accumulation. AA as well as many other endogenous (e.g., methylamine) and xenobiotic amines (e.g., benzylamine) are oxidized by dioxygen in the presence of SSAO, a group of poorly understood plasma circulating and membrane bound Cu-dependent enzymes, yielding an aldehyde, H2O2 and NH4+ ions. With AA, SSAO activity paradoxally produces the cytotoxic and genotoxic MG. AA bears an amino group vicinal to the carbonyl function and therefore is expected to undergo phosphate-catalyzed enolization and iron-catalyzed oxidation to yield reactive oxygen species (ROS), including HO• radicals. The present work aims to clarify the mechanisms by which AA undergoes direct and metal-catalyzed aerobic oxidation to yield deleterious ROS, with emphasis on the catalytic role of iron given its well-known implications in diabetes. In the present work we show that ROS generated through the aerobic oxidation of AA are able to induce damage in isolated rat liver mitochondria as well as in horse spleen ferritin (HoSF) and human ceruloplasmin (CP). The current findings of changes in HoSF and CP may contribute to explain intracellular iron-induced oxidative stress during AA accumulation in diabetes mellitus patients. (AU)