Toxic action of mimosine—I. Inhibition of mitosis and DNA synthesis of H.Ep-2 cell by mimosine and 3,4-dihydroxypyridine

doi:10.1016/0041-0101(71)90076-6

Toxicon

Volume 9, Issue 3, July 1971, Pages 241-247

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Abstract

The effect of mimosine, (β-N(3-hydroxy-4-pyridone)-α-amino propionic acid), and 3,4-dihydroxypyridine on cell growth, mitotic frequency, DNA, RNA and protein synthesis of H.Ep-2 cell cultures has been studied. Thymidine-H³, uridine-H³ and l-phenylalanine-C¹⁴ incorporation were measured in a liquid scintillation counter and thymidine-H³ uptake by an autoradiographic technique. Cell growth, mitotic frequency and thymidine-H³ incorporation were all decreased by the presence of mimosine or 3,4-dihydroxypyridine. The toxic effects of these compounds were decreased by the presence of Al³⁺. RNA synthesis was less inhibited than DNA synthesis and practically no inhibition of protein synthesis was observed in the presence of mimosine or 3,4-dihydroxypyridine.

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Production of reversible infertility in rats by feeding mimosine
Biochem. Pharmac.
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Archs Biochem. Biophys.
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C.S. Chen
I—Study on acid hydrolysis of mimosine; II—Toxicity of 3,4-dihydroxypyridine to rats
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There are more references available in the full text version of this article.

Cited by (44)

Iron
2021, Handbook on the Toxicology of Metals: Fifth Edition
Iron is the fourth most abundant metal on Earth. Iron can easily change valence and form complexes with oxygen, and iron-mediated reactions support the respiration of nearly all aerobic organisms. Unless appropriately shielded, iron catalyzes the formation of radicals that can damage biological molecules, cells, tissues, and entire organisms. Because of the inherent danger of iron, specialized molecules for the acquisition, transport, and storage of iron have evolved. Delivery of iron to most cells occurs following the binding of transferrin to transferrin receptors on the cell membrane. The transferrin-transferrin receptor complexes are then internalized by endocytosis and iron is released from transferrin by a process involving endosomal acidification and reduction. Extra iron is stored in ferritin. Intake of iron by the body is transported from guts to enterocytes through the natural resistance-associated macrophage protein/divalent metal transporter 1 and subsequently from enterocytes to the circulation through hepcidin-ferroportin complexes. Organisms and cells possess a limited ability to excrete excess iron. Cells are also equipped with a regulatory system that controls iron levels in the labile pool. Levels of iron modulate the capacity of iron regulatory proteins to bind to the iron-responsive elements in the untranslated regions of several mRNAs encoding proteins involved in iron metabolism, thus, control iron homeostasis at the cellular and organismal levels. Despite these homeostatic mechanisms, organisms can face the threat of either iron deficiency or iron overload. Acute iron overload from overdose is potentially life-threatening. Chronic iron overload leads to slowly developing damage to organs such as the heart, liver, and brain. Occupational inhalation exposures to iron may give rise to siderosis. Our developing knowledge of iron metabolism increasingly emphasizes both vital and threatening nature of this most important and abundant metal.
Potential toxic effects produced by L-mimosine in the thyroid and reproductive systems. Evaluation in male rats
2021, Toxicon
Citation Excerpt :
Goitre is an additional symptom that has been well described in ruminants; thus, ruminal microflora metabolizes L-mimosine to 3,4 DHP, which is unmistakably identified to be a potent goitrogenic (Hegarty et al., 1976; Holmes, 1980), being the product of conversion of 3,4 DHP by plant enzymes, the compound 2,3 DHP also a goitrogen (Paul, 2000). On the other hand, considering that L-mimosine can be broken down after harvesting by enzymes present in the plant tissue (Wee and Wang, 1987), the possibility of DHP intoxication in nonruminants should be considered (Tsai and Ling 1971; Prasad and Paliwal, 1989; Perry et al., 2005; Xuan et al., 2016). This assumption is reinforced by Tangendjaja and Lowry (1985), who associated the widespread goitre observed in people of Indonesia and the widespread use of young shoots, pods and green leucaena in salads.
Leucaena leucocephala is a worldwide plant used as forage; however, its use in animal production has been limited because of the presence of a toxic nonprotein amino acid, L-mimosine. L-mimosine exhibits negative effects not only in ruminants but also in monogastric animals; however, there is little information available on the effect of this amino acid in monogastric species. Thus, this study aimed to evaluate the general toxicity of L-mimosine in rats, as well as its effects on the endocrine and reproductive systems. L-mimosine was extracted from seeds of L. leucocephala that were administered orally by gavage to adult Wistar rats at different doses of 25, 40 and 60 mg/kg body weight/day for 28 days. The following parameters were evaluated: weight gain, feed intake, serum enzymes, histopathology (liver, kidney, thyroid, thymus, and spleen), serum hormones (testosterone, corticosterone, T3 and T4) and sexual behavior. No clinical signs of toxicity were observed in animals, but histopathology revealed consistent lesions in the thyroids. Additionally, rats exposed to L-mimosine presented low serum levels of testosterone, decreased mount numbers and increased mount intervals. Therefore, our study reinforces the assumption that L-mimosine has goitrogenic potential and causes impairment in male reproductive performance.
Iron
2015, Handbook on the Toxicology of Metals: Fourth Edition
Iron is the fourth most abundant metal in the Earth’s crust and the most abundant transition metal. Iron can easily change valence and form complexes with oxygen, and iron-mediated reactions support the respiration of nearly all aerobic organisms. However, unless appropriately shielded, iron catalyzes the formation of radicals that can damage biological molecules, cells, tissues, and entire organisms. Exposure to excess iron—typically from multiple blood transfusions over many years—can have numerous pathological consequences. In contrast, severe iron deficiency may also have serious health consequences. Because of the inherent danger of iron, specialized molecules for the acquisition, transport, and storage (ferritin) of iron in a soluble nontoxic form have evolved. Delivery of iron to most cells occurs following the binding of transferrin to transferrin receptors on the cell membrane. The transferrin-receptor complexes are then internalized by endocytosis and iron is released from transferrin by a process involving endosomal acidification and reduction. Iron is then transported through the endosomal membrane by the natural resistance-associated macrophage protein (NRAMP2/DMT-1; encoded by SLC11A2, previously NRAMP2) Fe(II) transporter. Importantly, this transporter is involved in the absorption of inorganic iron in the duodenum, a process facilitated by the ferric reductase, cytochrome b reductase 1/duodenal cytochrome b (Dcytb; encoded by DCYTB), which presumably provides Fe(II) for NRAMP2/DMT-1. Organisms and cells possess limited ability to excrete excess iron, and only some specialized cells have active mechanisms to export iron. Iron release from these “donor cells” (primarily enterocytes and macrophages that recycle hemoglobin iron) is mediated by ferroportin. The ferroxidase activity of copper-containing proteins, hephaestin and ceruloplasmin, facilitates the movement of iron across the membranes of enterocytes and macrophages, respectively. Cells are also equipped with a regulatory system that controls iron levels in the labile pool. Levels of iron modulate the capacity of iron-responsive element-binding proteins [IRE-BPs; also known as iron regulatory proteins (IRPs)] to bind to the iron-responsive elements (IREs) present in the untranslated regions of several mRNAs encoding proteins involved in iron metabolism (e.g. ferritin, transferrin receptor, DMT-1); these associations, or lack of them, in turn control the expression of these proteins. In fact, important information about regulation of iron metabolism came from studies of proteins (e.g. HFE, ferroportin, and hepcidin) encoded by genes, mutations in which cause different types of hereditary hemochromatoses. Despite these homeostatic mechanisms, organisms can face the threat of either iron deficiency or iron overload.
Acute iron overload resulting from unintentional or intentional overdose is potentially life threatening. Chronic iron overload leads to slowly developing (and, in extremis, lethal) damage to organs such as the heart and liver. However, the nature of the accumulated damage that eventuates in such organ failure is not yet fully understood. Additionally, occupational inhalation exposures to iron may give rise to siderosis, a benign condition easily diagnosed by chest X-ray. Our developing knowledge of iron metabolism increasingly emphasizes the simultaneously vital and threatening nature of this most important and abundant metal.
Iron homeostasis in breast cancer
2014, Cancer Letters
Citation Excerpt :
Some naturally occurring iron chelators have also some promising effects on breast cancer treatment. Mimosine, a toxic non-protein amino-acid found in the foliage and seeds of Leucaena glauca or Mimosa pudica [339], has shown to block cell cycle progression in MDA-MB-453 human breast cancer cells, through iron depletion, in a lower dosage than DFO [340]. In the last years, the interest on the phenolic extract of the turmeric Indian spice (diferuloymethane) has also increased, due to its potential as an anti-cancer agent [341,342].
Iron is an essential element and a critical component of molecules involved in energy production, cell cycle and intermediate metabolism. However, the same characteristic chemistry that makes it so biologically versatile may lead to iron-associated toxicity as a consequence of increased oxidative stress. The fact that free iron accumulates with age and generates ROS led to the hypothesis that it could be involved in the etiogenesis of several chronic diseases. Iron has been consistently linked to carcinogenesis, either through persistent failure in the redox balance or due to its critical role in cellular proliferation. Several reports have given evidence that alterations in the import, export and storage of cellular iron may contribute to breast cancer development, behavior and recurrence. In this review, we summarize the basic mechanisms of systemic and cellular iron regulation and highlight the findings that link their deregulation with breast cancer. To conclude, progresses in iron chelation therapy in breast cancer, as a tool to fight chemotherapy resistance, are also reviewed.
Iron
2014, Handbook on the Toxicology of Metals
Iron is the fourth most abundant metal in the Earth’s crust and the most abundant transition metal. Iron can easily change valence and form complexes with oxygen, and iron-mediated reactions support the respiration of nearly all aerobic organisms. However, unless appropriately shielded, iron catalyzes the formation of radicals that can damage biological molecules, cells, tissues, and entire organisms. Exposure to excess iron—typically from multiple blood transfusions over many years—can have numerous pathological consequences. In contrast, severe iron deficiency may also have serious health consequences. Because of the inherent danger of iron, specialized molecules for the acquisition, transport, and storage (ferritin) of iron in a soluble nontoxic form have evolved. Delivery of iron to most cells occurs following the binding of transferrin to transferrin receptors on the cell membrane. The transferrin-receptor complexes are then internalized by endocytosis and iron is released from transferrin by a process involving endosomal acidification and reduction. Iron is then transported through the endosomal membrane by the natural resistance-associated macrophage protein (NRAMP2/DMT-1; encoded by SLC11A2, previously NRAMP2) Fe(II) transporter. Importantly, this transporter is involved in the absorption of inorganic iron in the duodenum, a process facilitated by the ferric reductase, cytochrome b reductase 1/duodenal cytochrome b (Dcytb; encoded by DCYTB), which presumably provides Fe(II) for NRAMP2/DMT-1. Organisms and cells possess limited ability to excrete excess iron, and only some specialized cells have active mechanisms to export iron. Iron release from these “donor cells” (primarily enterocytes and macrophages that recycle hemoglobin iron) is mediated by ferroportin. The ferroxidase activity of copper-containing proteins, hephaestin and ceruloplasmin, facilitates the movement of iron across the membranes of enterocytes and macrophages, respectively. Cells are also equipped with a regulatory system that controls iron levels in the labile pool. Levels of iron modulate the capacity of iron-responsive element-binding proteins [IRE-BPs; also known as iron regulatory proteins (IRPs)] to bind to the iron-responsive elements (IREs) present in the untranslated regions of several mRNAs encoding proteins involved in iron metabolism (e.g. ferritin, transferrin receptor, DMT-1); these associations, or lack of them, in turn control the expression of these proteins. In fact, important information about regulation of iron metabolism came from studies of proteins (e.g. HFE, ferroportin, and hepcidin) encoded by genes, mutations in which cause different types of hereditary hemochromatoses. Despite these homeostatic mechanisms, organisms can face the threat of either iron deficiency or iron overload.
Acute iron overload resulting from unintentional or intentional overdose is potentially life threatening. Chronic iron overload leads to slowly developing (and, in extremis, lethal) damage to organs such as the heart and liver. However, the nature of the accumulated damage that eventuates in such organ failure is not yet fully understood. Additionally, occupational inhalation exposures to iron may give rise to siderosis, a benign condition easily diagnosed by chest X-ray. Our developing knowledge of iron metabolism increasingly emphasizes the simultaneously vital and threatening nature of this most important and abundant metal.
Iron
2007, Handbook on the Toxicology of Metals, Third Edition

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Abstract

References (13)

Production of reversible infertility in rats by feeding mimosine

Biochem. Pharmac.

The effect of elevated temperature on the mimosine content and toxicity of Koa Haole (Leucaena glauca)

Archs Biochem. Biophys.

I—Study on acid hydrolysis of mimosine; II—Toxicity of 3,4-dihydroxypyridine to rats

Inhibition of growth of hair by mimosine

Nature, Lond.

Reaction of sheep to the consumption of Leucaena glauca and to its toxic principle mimosine

Aust. J. agric. Res.

Studies on free amino acid in the seeds of Leucaena glauca Benth—III. Biological study on mimosine

J. Formosan med. Ass.

Cited by (44)

Iron

Potential toxic effects produced by L-mimosine in the thyroid and reproductive systems. Evaluation in male rats

Iron

Iron homeostasis in breast cancer

Iron

Iron