Bioquímica e ação citotóxica de alfa-aminocetonas endógenas

Abstract

BIOCHEMISTRY AND CYTOTOXICITY OF α-AMINOKETONES. α-Aminoketones are expected to undergo enolization and subsequent aerobic oxidation yielding oxyradicals and highly toxic a-oxoaldehydes. Our interest has been focused on two endogenous a-aminoketones: 5-aminolevulinic acid (ALA) and aminoacetone (AA), accumulated in porphyrias and diabetes mellitus, respectively, and recently implicated as contributing sources of oxyradicals in these diseases. The final oxidation product of ALA, 4,5-dioxovaleric acid (DOVA), is able to alkylate DNA guanine moieties and expected to promote protein cross-linking. Methylglyoxal (MG), the final oxidation product of AA, is also highly cytotoxic and able to aggregate protein molecules. This review covers chemical and biochemical aspects of these α-aminoketones and their putative roles in the oxidative stress associated with porphyric disorders and diabetes.

l-Glutamine Supplementation Prevents Myenteric Neuron Loss and Has Gliatrophic Effects in the Ileum of Diabetic Rats

“…The increased synthesis of glutathione becomes even more important when considering that glutathione levels are reduced in diabetes mellitus. Several factors are involved in the reduction of endogenous glutathione, for example reduction in the NADPH-dependent conversion of oxidized glutathione to reduced glutathione by glutathione reductase, which is found in low concentrations because of competition with the polyol pathway (which is also NADPH-dependent) [48], increased activity of glyoxalase I (i.e., an enzyme that uses reduced glutathione), and reduction in glyoxalase II activity (i.e., an enzyme responsible for methylglyoxal degradation) [49]. The ganglionic density of HuC/D-immunoreactive neurons was similar to the neuronal density obtained per unit area in diabetic animals (group D; i.e., a significant 18.28% reduction was observed in the number of neurons per myenteric ganglion compared with normoglycemic animals in group N).…”

Diabetic Rats Supplemented with L-Glutamine: A Study of Immunoreactive Myosin-V Myenteric Neurons and the Proximal Colonic Mucosa

“…This happens due to (1) a reduction in the conversion of oxidized glutathione to reduced glutathione by the NADPH-dependent enzyme glutathione reductase, once NADPH is at low concentrations due to competition with the polyol pathway (also dependent on NADPH) [12,13]; and (2) an increase in the activity of glyoxalase I, a reduction in the operation of glyoxalase II (enzymes responsible for methylglyoxal degradation), and, therefore, glutathione depletion [39].…”

Desenvolvimento De Estratégias Farmacoterapêuticas Para O Infarto Agudo Do Miocárdio: Desafios E Novas Perspectivas, Parte Ii

“…Entretanto, como visto na parte I deste capítulo a formação das AGE´s constituem um dos fatores mais importante para o desenvolvimento das síndromes metabólicas, sendo responsáveis pelas complicações e agravos do Diabetes mellitus, bem como, da gênese das vasculopatias por causas glicídicas. Também já é reportado o Cross link entre o processo de redução de açúcares e sua associação com resíduos de aminoácidos, formando bases de Schiff e produtos de Amadori catalisados enzimaticamente, gerando AGE´s e aumento das espécies reativas de oxigênio, com alto potencial citotóxico (Dutra & Bechara, 2005). Não obstante, tomando por base a formação das AGE´s como novos alvos farmacológicos, o surgimento de moléculas bioativas capazes de modular ações sobre as AGE´s e reduzir seus níveis circulantes, constituem um curioso ponto de partida para o desenvolvimento de novos fármacos, que possam contribuir para a farmacoterapia cardiometabólica.…”