A comparison of the accumulation of ricin by hepatic parenchymal and non-parenchymal cells and its inhibition of protein synthesis

Skilleter, David N.; Paine, Alan J.; Stirpe, Fiorenzo

doi:10.1016/0304-4165(81)90264-6

Cited by 66 publications

(37 citation statements)

References 27 publications

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“…In agreement with earlier experiments by Fodstad et al [5] and Skilleter et al [7], '251-ricin injected into rats was found to be rapidly removed from the bloodstream by the liver and, to a much lesser extent, by the spleen and lungs. Fractionation of the liver into its component cell types confirmed that it was the non-parenchymal cells that were primarily responsible for the entrapment of the toxin.…”

Section: Vitrosupporting

confidence: 80%

Modification of the carbohydrate in ricin with metaperiodate — cyanoborohydride mixtures

Thorpe

Detre

Foxwell

et al. 1985

European Journal of Biochemistry

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108

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Attempts to target antibody-ricin conjugates (immunotoxins) to designated cell types in vivo may be thwarted by their rapid clearance by hepatic reticuloendothelial cells which have receptors that recognise oligosaccharide side chains on the toxin. The B-chain of ricin contains high mannose type oligosaccharides and the A-chain contains a complex unit (GlcNAc)2-Fuc-Xyl-(Man)4-6, all of which potentially could be recognised by the reticuloendothelial system.Treatment of ricin with a mixture of sodium metaperiodate and sodium cyanoborohydride at pH 3.5 resulted in oxidative cleavage of the carbohydrates and reduction of the aldehyde groups thus formed to primary alcohols. By conducting the modification procedure at acidic pH, both the possibility of Schiff s base formation between the aldehyde groups and amino groups in the protein and the possibility of non-specific oxidation of amino acids were minimised. The extent of the carbohydrate modification depended on the duration of treatment, resulting maximally in the destruction of 13 of the 18 mannose residues and of all xylose and fucose.The toxicity of the modified toxin to cells in culture declined by up to 90% as the carbohydrate was destroyed. This was not due to a reduced ability of the B-chain to bind to cells or of the A-chain to inactivate ribosomes. In contrast to the in vitro results, the toxicity of the modified toxin to mice and rats was elevated by up to fourfold. The modification greatly reduced the clearance of the toxin by non-parenchymal cells in the liver and prevented the damage to hepatic Kupffer and sinusoidal cells and to the red pulp of the spleen that is inflicted by the native toxin. The elevated toxicity to animals appears to be because the modified toxin evades the reticuloendothelial system and persists in the bloodstream for longer periods, thus resulting in lethal damage to vital tissues in the animal at lower dosage.The results suggest that immunotoxins prepared from modified ricin would not be readily cleared by the reticuloendothelial system and so be more effective at killing their target cells.Attempts have been made in several laboratories to target ricin to designated cell types in animals by linking it to specific antibodies (reviewed in [l -31).Ricin, the toxin from the castor bean, is a glycoprotein comprising two polypeptide chains, A and B, joined by a disulphide bond. The B-chain binds to galactose-containing glycoproteins and glycolipids on cell surfaces and the A-chain then penetrates the membrane (probably from an endocytic vesicle) and kills the cell by inactivating ribosomes (reviewed in 141).When injected intravenously into rats or mice, rich rapidly accumulates in the liver and, to a lesser extent, in the spleen [5] wise be cleared from the bloodstream in animals and prompted us to devise ways of modifying the carbohydrate side chains in the toxin to prevent hepatic recognition. A previous attempt by Simeral et al. [8] to destroy the carbohydrate in ricin using sodium metaperiodate resulted in virtually complete ...

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Section: Vitrosupporting

confidence: 80%

Modification of the carbohydrate in ricin with metaperiodate — cyanoborohydride mixtures

Thorpe

Detre

Foxwell

et al. 1985

European Journal of Biochemistry

Self Cite

108

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“…Only a small proportion seems to reach the bloodstream and the inner organs. In the liver, phagocytotic Kupffer cells and sinusoidal endothelial cells have been reported to be the main targets [300,301,302,303,304]. Indeed, hepatic Kupffer and sinusoidal endothelial cells as well as other phagocytotic cells (e.g., macrophages, granulocytes, dendritic cells) constitute the forefront in immunological defense and do not only express glycolipids and glycoproteins on their cell surface, but are also equipped with lectin receptors which enable the rapid uptake of ricin into the cells [305,306].…”

Section: Detection Of Ricin or Ricinus Communismentioning

confidence: 99%

Ricinus communis Intoxications in Human and Veterinary Medicine—A Summary of Real Cases

Worbs

Köhler

Pauly

et al. 2011

Toxins

200

177

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Accidental and intended Ricinus communis intoxications in humans and animals have been known for centuries but the causative agent remained elusive until 1888 when Stillmark attributed the toxicity to the lectin ricin. Ricinus communis is grown worldwide on an industrial scale for the production of castor oil. As by-product in castor oil production ricin is mass produced above 1 million tons per year. On the basis of its availability, toxicity, ease of preparation and the current lack of medical countermeasures, ricin has gained attention as potential biological warfare agent. The seeds also contain the less toxic, but highly homologous Ricinus communis agglutinin and the alkaloid ricinine, and especially the latter can be used to track intoxications. After oil extraction and detoxification, the defatted press cake is used as organic fertilizer and as low-value feed. In this context there have been sporadic reports from different countries describing animal intoxications after uptake of obviously insufficiently detoxified fertilizer. Observations in Germany over several years, however, have led us to speculate that the detoxification process is not always performed thoroughly and controlled, calling for international regulations which clearly state a ricin threshold in fertilizer. In this review we summarize knowledge on intended and unintended poisoning with ricin or castor seeds both in humans and animals, with a particular emphasis on intoxications due to improperly detoxified castor bean meal and forensic analysis.

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“…MR was first identified on alveolar macrophages (Largent et al 1984; Shepherd et al 1981), and later discovered to be expressed on a variety of cell types, including hepatic sinusoidal endothelial cells (HSEC) and Kupffer cells. It has been noted that 125 I-labeled ricin accumulates in rat liver non-parenchymal cells (i.e., Kupffer cells) to a much greater extent than parenchymal cells, and that this accumulation could be inhibited by d -mannose (Magnusson and Berg 1993; Magnusson et al 1991, 1993; Skilleter et al 1981). While these studies support a role of the MR in promoting toxicity of ricin in vivo, recent results from ricin challenge studies of MR deficient mice revealed the opposite outcome.…”

Section: Ricin Toxicity Structure and Functionmentioning

confidence: 99%

Immunity to Ricin: Fundamental Insights into Toxin–Antibody Interactions

O’Hara

Yermakova

Mantis

2011

Current Topics in Microbiology and Immunology

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Ricin toxin is an extraordinarily potent inducer of cell death and inflammation. Ricin is also a potent provocateur of the humoral immune system, eliciting a mixture of neutralizing, non-neutralizing and even toxin-enhancing antibodies. The characterization of dozens of monoclonal antibodies (mAbs) against the toxin's enzymatic (RTA) and binding (RTB) subunits has begun to reveal fundamental insights into the underlying mechanisms by which antibodies neutralize (or fail to neutralize) ricin in systemic and mucosal compartments. This information has had immediate applications in the design, development and evaluation of ricin subunit vaccines and immunotherapeutics.

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A comparison of the accumulation of ricin by hepatic parenchymal and non-parenchymal cells and its inhibition of protein synthesis

Cited by 66 publications

References 27 publications

Modification of the carbohydrate in ricin with metaperiodate — cyanoborohydride mixtures

Modification of the carbohydrate in ricin with metaperiodate — cyanoborohydride mixtures

Ricinus communis Intoxications in Human and Veterinary Medicine—A Summary of Real Cases

Immunity to Ricin: Fundamental Insights into Toxin–Antibody Interactions

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