Disease relevance of Divicine

• Divicine has long been thought to be a mediator of an acute hemolytic crisis, known as favism, in susceptible individuals who ingest fava beans (Vicia faba) [1].
• Incubation of glutathione (GSH) depleted mouse erythrocytes with the oxidants phenylhydrazine, acrolein, divicine and isouramil resulted in the release of free iron and in lipid peroxidation and hemolysis [2].
• The toxicity of dialuric acid to pancreatic beta cells, and the haemolytic action of divicine and isouramil involve auto-oxidation and redox cycling reactions [3].

High impact information on Divicine

• Specifically, autoxidizing divicine inactivated procalpain, the proenzyme species of calcium-activated cytosolic neutral proteinase, or calpain [4].
• That the pyrimidine product of this process (when carried out in the presence of 2-mercaptoethanol) is 2,6-diamino-5-hydroxy-4-pyrimidinone (divicine) is further confirmed by mass spectrometry of an isolated t-butyldimethylsilyl derivative [5].
• The majority of divicine isolated from phenylalanine hydroxylase incubations with o-methyl substrate analog was labeled with oxygen from 18O2 [5].
• The position of the isotope was unambiguously assigned to the 5-hydroxyl group by the simultaneous use of [18O] TP and 18O2, the divicine from which was found to be doubly labeled. o-Methylphenylalanine stimulates a rate of cofactor oxidation at least 10-fold greater than its own rate of hydroxylation [5].
• Iron release and membrane damage in erythrocytes exposed to oxidizing agents, phenylhydrazine, divicine and isouramil [6].

Chemical compound and disease context of Divicine

• Although the fava bean pyrimidine aglycones, divicine and isouramil, have been implicated in the onset of favism in humans, the lack of a well-defined experimental animal model for favism has hampered progress in elucidating the mechanism underlying hemotoxicity [7].
• The fava bean pyrimidine aglycone divicine has been identified as a hemotoxic constituent; however, its mechanism of toxicity remains unknown [8].
• The effects of divicine (DV), one of its degradation products ("blue DV"), and H2O2 on normal and pre-treated rat erythrocyte (RBC) reduced glutathione (GSH) content, spontaneous hemolysis at different tonicity levels, optical absorption spectrum of the hemolysate, as well as on their morphology were investigated [9].

Biological context of Divicine

• These results support the view that divicine plays a toxic role in the pathogenesis of favism and suggest that acute electrolyte imbalances, mostly affecting calcium homeostasis, are involved in the mechanisms of erythrocyte damage and destruction in this hemolytic disease [10].
• Activity of divicine in Plasmodium vinckei-infected mice has implications for treatment of favism and epidemiology of G-6-PD deficiency [11].
• Role of hemin in oxidative stress induced by divicine in vitamin E-deficient rats [12].

Anatomical context of Divicine

• Divicine induces calcium release from rat liver mitochondria [13].
• Membrane modifications by divicine, contained in fava beans, followed by osmotic shrinkage in the kidney and/or squeezing in the microcirculation are proposed as the cause of MCB during the favic crisis [14].
• Cyanide-insensitive respiration indicates redox cycling of divicine in mitochondria [13].
• Inactivation of Ca2+-ATPase is apparently unrelated to the cellular GSH system, to the proteolytic machinery of mature erythrocytes, and to calmodulin, and also occurs in hemoglobin-free, unsealed erythrocytes membranes at 50-100 microM concentrations of divicine [10].
• Iron release and oxidant damage in human myoblasts by divicine [15].

Associations of Divicine with other chemical compounds

• However, divicine and isouramil produced alterations of membrane proteins, such as spectrin and band 3, as well as formation of senescent cell antigen [2].
• In the presence of oxygen divicine re-oxidizes both NADPH and NADH, whereby a red-ox cycling is perpetuated between hydroquinonic and quinonic species of divicine itself [16].
• Restoration of normal levels of glucose-6-phosphate dehydrogenase activity by means of entrapment of homogeneous human glucose-6-phosphate dehydrogenase in the deficient red cells results in normal stability of intracellular reduced glutathione; decreased susceptibility of procalpain to inactivation by autoxidizing divicine [17].
• The effects of GSH on the autoxidation of the fava bean pyrimidine aglycones, divicine and isouramil, and on acid-hydrolyzed vicine (provisional identification 2-amino-4,5,6-trihydroxypyrimidine) have been studied [18].
• Similar modifications of the two enzyme activities are observed after treatment of normal red blood cells with high concentrations of divicine and ascorbate, which are redox compounds that are contained in fava seeds [19].

Gene context of Divicine

• These data demonstrate that a favic response can be induced in G6PD-normal rats treated with divicine, and that hemolytic activity can be reproduced in isolated red cells under conditions that will allow a direct examination of the mechanism underlying this hemotoxicity [7].
• Inhibition of both mitochondrial glutathione peroxidase and glutathione reductase slows down divicine-induced calcium release [13].
• Inactivation of red cell glutathione peroxidase by divicine and its relation to the hemolysis of favism [20].
• In the present study we have assayed the effect of divicine in G6PD-deficient red blood cells in the presence of deferoxamine (iron-chelating drug) and NaN3 (inhibitor of catalase) [21].
• The one having maximum absorption at 305 nm is susceptible of reduction by glutathione reductase, while the adduct with maximum absorption at 320 nm is stable and is likely to represent a dead-end complex of divicine [16].

Analytical, diagnostic and therapeutic context of Divicine

• The stability and redox behavior of divicine, under physiological conditions, were examined by HPLC and cyclic voltammetry [1].
• Examination of divicine-treated red cells by scanning electron microscopy revealed transformation of the cells to an extreme echinocytic morphology [8].
• Intravenous injection of divicine into mice infected with Plasmodium vinckei rapidly killed the parasites and caused haemolysis [11].

References