Metabolic effects of pyrimidines derived from fava bean glycosides on human erythrocytes deficient in glucose-6-phosphate dehydrogenase

Mager, J.; Glaser, Gad; Razin, A.; Izak, G.; Bien, Shlomo; Noam, M.

doi:10.1016/0006-291x(65)90352-9

Cited by 109 publications

(45 citation statements)

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“…When glucose-deprived red blood cells are incubated in vitro in the presence of millimolar amounts of isouramil or divicine, the content of the reduced glutathione (GSH) in the red blood cells shows a rapid decline followed by a pronounced fall of the intracellular ATP level [5]. Furthermore, treatment for over 60 min with isouramil caused a permanent cellular damage that was expressed in the inability of the cells to restore their normal GSH levels, even after addition of glucose and removal of the aglycome from the system [I, 21. In the present communication the molecular mechanism involved in the deleterious effect of isouramil on the red blood cells is investigated.…”

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confidence: 99%

The Chemistry of Favism‐Inducing Compounds

Chevion

Navok

Glaser

et al. 1982

European Journal of Biochemistry

105

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Isouramil and divicine are pyrimidine aglycones of two glucosides found in broad beans. They have been shown to be strong reducing agents. Their reaction with oxygen in a (gas) saturated solution, 26°C, is characterized by τ1/2= 1 min and 3 min respectively. Hydrogen peroxide is formed in this reaction stoichiometrically (1:1). The pyrimidines lose two hydrogen and form an intermediate that is structurally analogues to alloxan. This intermediate is not stable, and in the absence of reducing agents it decomposes, possibly by ring‐cleavage. In the presence of reduced glutathione the intermediate is reduced and can now react with oxygen once again. Thus, the pyrimidines cycle between the two states and the net reaction is the catalytic oxidation of glutathione by molecular oxygen; in each cycle 4 molecules of glutathione are dissipated. The possible involvement of these pyrimidines in the pathogenesis of favism may be in a similar mechanism. Red blood cells deficient in glucose‐6‐phosphate dehydrogenase cannot cope with such an oxidative challenge exerted by the pyrimidines. Consequently an irreversible cellular damage can take place leading to the enhanced sequestration of these red blood cells by the reticuloendothelial system.

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confidence: 99%

The Chemistry of Favism‐Inducing Compounds

Chevion

Navok

Glaser

et al. 1982

European Journal of Biochemistry

105

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“…9 We have termed pharmacogenomic concepts linked to drug metabolism PGX m , which corresponds to genetic variants that determine drug disposition, also referred to as drug pharmacokinetics.…”

Section: Precision Medicine In Oncologymentioning

confidence: 99%

“…8 This phenotype was later attributed to a glucose-6-phosphate dehydrogenase deficiency. 9 We have termed pharmacogenomic concepts linked to drug metabolism PGX m , which corresponds to genetic variants that determine drug disposition, also referred to as drug pharmacokinetics. 10,11 The conversion of a parent compound to an inactive metabolite or to one that is more easily excreted and the conversion of a prodrug to its active metabolite are examples of PGX m .…”

Section: Precision Medicine In Oncologymentioning

confidence: 99%

Somatic Mutation Analysis of Human Cancers: Challenges in Clinical Practice

Tsongalis

Coleman

2017

The Journal of Clinical Pharma

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Somatic mutation analysis of human cancers has become the standard of practice. Whether screening for single gene variants or sequencing hundreds of cancer-related genes, this genomic information is the basis for precision medicine initiatives in oncology. Genomic profiling results in information that allows oncologists to make a more educated selection of appropriate therapeutic strategies that more often combine traditional cytotoxic chemotherapy and radiation with novel targeted therapies. Here we discuss the nuances of implementing somatic mutation testing in a clinical setting. Keywordsclinical genomics, oncology, precision medicine, pharmacogenomics, somatic mutation Novel therapies, including the use of directed monoclonal antibodies, tyrosine kinase inhibitors, and immunotherapies, have come to fruition as our understanding of the etiology of human cancer expands. From the identification of the first oncogenes and tumor-suppressor genes to current full gene sequencing for the identification of somatic mutations, knowledge of tumor-cell genetic variant profiles has become critical to the management of the cancer patient.1-3 One projection of the Human Genome Project was to gain a more fundamental understanding of human disease at the genomic level such that novel therapeutics could be designed to provide a more personalized approach to disease management. The identification of numerous driver mutations in various human cancers, which are causally implicated in establishing growth advantages to a cell, have also become the target of novel therapies that confer more efficacious outcomes. 4,5 The rapid development of targeted therapies is also resulting in more advanced and focused clinical trial designs whereby testing protocols aim to match patients whose tumors harbor specific somatic mutations with those specific therapies targeting the gene or pathway affected. 6,7 Precision Medicine in OncologyWith respect to the cancer patient, the concept of targeted or individualized therapy can include 2 aspects of what is often termed pharmacogenomics. The first is the more traditional concept that encompasses how an individual may metabolize, absorb, transport, and excrete therapeutic drugs differently based on polymorphisms in the genes that code for these functions. This type of individual variation in metabolism was first described in 510 BC when Pythagoras recognized hemolytic anemia developing in some individuals who consumed fava beans.8 This phenotype was later attributed to a glucose-6-phosphate dehydrogenase deficiency. 9 We have termed pharmacogenomic concepts linked to drug metabolism PGX m , which corresponds to genetic variants that determine drug disposition, also referred to as drug pharmacokinetics.10,11 The conversion of a parent compound to an inactive metabolite or to one that is more easily excreted and the conversion of a prodrug to its active metabolite are examples of PGX m .PGX t is the second aspect of pharmacogenomics that involves the selection of a therapeutic drug based on the...

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“…From studies on the action of vicine and convicine aglycons* (Lin and Ling, 1962a, b, and c;Mager et al, 1965) on GSH in vitro, it was then suggested that the 'haemolytic principle' of Vicia faba could be identified with some of these substances. However, the glycosides vicine and convicine, both of which are present in Vicia faba, are inactive on GSH (Mager et al, 1965) and it is not known whether the relevant aglycons are present in the extracts of broad beans tested in vitro.…”

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Favism: Current Problems and Investigations

Bottini¹

1973

Journal of Medical Genetics

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Summary. Haemolytic favism is a severe, acute anaemia which occurs in glucose-6-phosphate dehydrogenase deficient individuals, usually following the ingestion of Vicia faba seeds. Current interest is focused on the nature of the active substances of Vicia faba and on the causes of the varying susceptibility among G6PD-deficient individuals to episodes of severe haemolysis.The results of experiments in vitro favour the hypothesis that Vicia faba contains several active substances which may act in a synergistic way.Red cell acid phosphatase and thalassaemia genes appear to play a remarkable role in conditioning the susceptibility to severe haemolysis in G6PD-deficient subjects.In addition to erythrocyte enzymes and to enzymes which intervene in the absorption and metabolism of the active substances of Vicia faba, another field for future investigations may be that of plasma factors which influence the stability of reduced glutathione in the red cells.

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Metabolic effects of pyrimidines derived from fava bean glycosides on human erythrocytes deficient in glucose-6-phosphate dehydrogenase

Cited by 109 publications

References 9 publications

The Chemistry of Favism‐Inducing Compounds

The Chemistry of Favism‐Inducing Compounds

Somatic Mutation Analysis of Human Cancers: Challenges in Clinical Practice

Favism: Current Problems and Investigations

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