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First draft prepared by Mike Bolger 1Raymond D. Riley 7Gordon Shephard 4 and Gerrit J. Results of surveys for fumonisin B 1 Appendix B. Results of surveys for fumonisin B 2 Appendix C. Results covehin surveys for fumonisin B 3.
The Committee evaluated fumonisins B 1B 2and B 3 at the request of the Codex Committee on Food Additives and Contaminants; these toxins had not been evaluated previously by the Committee. Ina monograph on fumonisin B 1 was published WHO, awhich provided much of the information used in this evaluation. Fumonisins are fungi produced by fungi of the genus Fusarium.
The only species that produce significant quantities of fumonisins are Fusarium verticillioides Sacc. At least 10 other Fusarium species also produce these toxins.
These species cause Fusarium kernel rot of maize, an important disease in hot climates. A strong relationship also exists between insect damage and Fusarium kernel rot due to other Fusarium species, such as F.
Temperature stress may also play a role, especially in cultivars grown outside their area of adaptation. Except under extreme conditions, the concentrations of fumonisins do not increase during grain storage. Formation of fumonisins in the field correlates with the occurrence of F. Fumonisins are widely distributed geographically, and their natural occurrence in maize has been reported in many areas of the world.
Of particular concern are the high concentrations found in maize produced and consumed by particular subpopulations, such ccovenin subsistence farmers. Considerable annual variations in contamination have been noted. Fumonisins occur infrequently in other foods, such as sorghum, asparagus, rice, beer, and mung beans. Fumonisins are a group of structurally related compounds. Fumonisin B 1 is the diester of propane-1,2,3-tricarboxylic acid and 2 S -amino S ,16 R -dimethyl- 3S ,5 R ,10 R ,14 S15R -pentahydroxyeicosane in which the C and C hydroxy groups are esterified with the terminal carboxy group of propane-1,2,3-tricarboxylic acid.
Fumonisin B 2 is the C deoxy analogue of fumonisin B 1 in which the corresponding stereogenic units on the eicosane backbone have the same configuration. The full stereochemistry of fumonisin B 3 and B 4 is unknown, but the amino terminal of fumonisin B 3 covsnin the same absolute covnein as that of fumonisin B 1.
As most biological data cobenin available on fumonisin B 1and maize is the major source 47 intake, the Committee focused its evaluation on toxicological studies of fumonisin B 1 and on studies of intake of contaminated maize and maize products. In many studies, culture materials and naturally contaminated maize were used, which can contain several other fumonisins, primarily fumonisins B 2 and B 3. The toxicological profiles of these toxins are very similar to that of fumonisin B 1.
Various chemical derivatives of fumonisins have been tested in a number of biological systems to gain insight into structure—activity relationships. Briefly, the fumonisins of the B series that have been investigated are more toxic in vivo than their hydrolysed or N -acetylated counterparts. The free amino group appears to covvenin a specific role in the biological activity of fumonisin B 1.
A thorough review of the biochemical aspects of fumonisin B 1 is contained in Fumonisin B 1 Environmental Health Criteriapublished by WHO aand much of what follows is derived from that review, with relevant new publications. With a few exceptions, only references that were not included in that monograph, recent or critical reviews, or studies with stated doses are cited here. In many studies on fumonisins in animals in vivo, culture materials or naturally contaminated maize were used in which not only fumonisin B 1 but also other fumonisins primarily ccovenin B 2 and B 3 can be found.
Various chemical derivatives of fumonisins have been studied in several biological systems to gain insight into the structural requirements of fumonisin-induced toxicity and biochemical mechanisms in vivo see WHO, a, pp. The free amino group has an important role, as the N -acetyl derivatives are less toxic in primary hepatocytes and hydrolysed fumonisin B 1 is more toxic. The lesser toxicity of hydrolysed fumonisin B 1 in rat liver is not due to reduced absorption. The fungus previously known as F.
In rats and most other animals, the kinetics of absorption of fumonisin B 1 indicates rapid distribution and elimination that is adequately described by a two- or three-compartment model most recently, Martinez-Larranaga et al.
In rats treated by gavage, more hydrolysed [ 14 C]fumonisin B 1 was excreted in urine than [ 14 C]fumonisin B 1 or the [ 14 C]fumonisin B 1 —fructose adduct. The authors concluded that hydrolysed fumonisin B 1 was better absorbed than fumonisin B 1although the biliary excretion of the two fumonisins was similar Dantzer et al. While fumonisin B 1 was distributed to most tissues, the liver and kidney retained most of the absorbed material, the liver retaining more toxin than covenib kidney in some studies and the inverse in others.
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clvenin This study confirmed previous reports that fumonisin B 1 persists in rat liver and kidney much longer than in plasma. The material retained in liver and kidney is primarily unmetabolized fumonisin B 1as shown in several studies of the persistence in kidney of free sphinganine a biomarker for fumonisin.
Thus, while fumonisin B 1 is eliminated rapidly, the concentration of the biomarker in rat kidney but not liver is more persistent most recently, Enongene et al. In pregnant rats, low concentrations of fumonisin B 1 were recovered in uteri 0. Similar results were reported in rabbits. There is also little evidence of significant transfer during lactation. For example, no fumonisin B 1 was detected in the milk of lactating sows fed diets containing non-lethal concentrations of fumonisin B 1and there was no evidence of toxicosis in their suckling piglets.
4744 a study in which lactating cows were given fumonisin B 1 intravenously, the carry-over rate into the milk reached a maximum of 0. The finding that little fumonisin B 1 is retained in tissues, milk, or eggs has led to the conclusion that fumonisin residues in food products derived from animals are insufficient to make them injurious to consumers.
After intraperitoneally or intravenously administered fumonisin B 1 has been distributed, its initial elimination is rapid, with no evidence of metabolism.
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Covwnin vervet monkeys Cercopithecus aethiops treated intraperitoneally with fumonisin B 2elimination was rapid and followed a bi-exponential pattern half-time, 18 minsimilar to 4474 of the elimination of fumonisin B 1 half-time, 40 min. The elimination kinetics in non-human primates after oral dosing has not covenib determined, but peak plasma concentrations of fumonisin B 1 and B 2 occurred 1 to several hours after a dose of 7.
Thus, the elimination kinetics after oral dosing is not easily described, unlike that of intraperitoneal or intravenous dosing. There is little or no evidence that fumonisins are metabolized in vitro or in vivo in animals, even though they are clearly excreted in bile. A study in which primary hepatocytes were exposed to [ 14 C]fumonisin B 1 showed that the toxin is associated with 977 the soluble and the insoluble membrane compartments of the cell, and no metabolites were detected after a h incubation.
Incubation with rat liver microsomal preparations also showed no metabolism by cytochrome P CYPmicrosomal esterase, or any other microsomal enzyme. Incubation with a triglyceride hepatic endothelial lipase or a porcine pancreatic lipase also did not result in hydrolysis of the tricarboxylic acid moieties of fumonisin B 1. Several studies in which 447 routes of exposure and different animal species were used showed that fumonisins are excreted primarily in the faeces, either unchanged or with loss of one or both of the tricarboxylic acid side-chains.
The material excreted in bile is still biologically covenn, since fumonisin B 1 given subcutaneously to mice rapidly entered the small intestine, where it inhibited ceramide synthase Enongene et al.
Loss of the tricarboxylic acid side-chains probably occurs in the coveniin, since after partial hydrolysis resulting in removal of only one of the two side-chains and full hydrolysis fumonisin B 1 is recovered in the faeces but not in the bile. Most of the hydrolysed fumonisin B 2 coenin present as a mixture of the two possible partially hydrolysed forms, while fully hydrolysed fumonisin B 2 was a minor constituent.
No hydrolysis products were found in urine, confirming that fumonisin was hydrolysed in the gut, probably by microbial degradation. While there is no evidence that fumonisin is metabolized by CYP enzymes, some studies have shown that fumonisins can alter their activity, and this observation 977 confirmed in vitro and in vivo Merrill et al. In some studies, the effects on CYP activity have been shown to be the result of fumonisin-induced alterations in sphingolipid metabolism Merrill et al.
For example, in HepG2 cells, fumonisin B 1 inhibited the induction of CYP 1A1 which metabolizes aryl hydrocarbons such as methylcholanthrene Merrill et al.
The inhibition of CYP 2C11 was attributed to suppression of protein kinase activity due to inhibition of sphingolipid biosynthesis.
Sphingosine, a sphingolipid that accumulates in animals exposed to fumonisin B 1was also shown to inhibit CYP 2C11 in rat hepatocytes Merrill et al. While there is little evidence that absorbed fumonisins are metabolized in animals, removal of the tricarboxylic acid side-chains producing hydrolysed fumonisin B 1 converts this inhibitor of ceramide synthase into a substrate for the enzyme.
The product of this reaction, N -palmitoyl-hydrolysed fumonisin B 1also inhibits ceramide synthase in vitro. It is not known whether this product is formed in vivo, but it is more toxic than fumonisin B 1 or hydrolysed fumonisin B 1 for HT cells Merrill et al. Since hydrolysed fumonisin B 1 and hydrolysed fumonisin B 2 are major breakdown products in nixtamalized maize products and are also produced in the gut from fumonisin B 1 and B 2the toxicity of the hydrolysed toxins should be addressed.
Several biochemical reactions have been proposed to explain all or some of the toxic effects of fumonisins in animals.
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Two of them invoke disruption of lipid metabolism as the initial site of action, and they are similar in other respects Gelderblom et al. The first proposed lipid-based mechanism involves inhibition of ceramide synthase, a key enzyme in the biosynthesis of sphingolipids reviewed extensively covenun WHO, a.
Cofenin second mechanism involves changes in the polyunsaturated fatty acid and phospholipid pools. Both lead ultimately to lipid-mediated alterations in signalling and metabolic pathways crucial to cell growth, death, and differentiation. Selected biochemical 9 for the toxicity of fumonisin B 1 in animal models in which the proposed biochemical action has been shown to be related to specific effects.
Also, increased free sphingoid bases and decreased sphingomyelin. Selected biochemical mechanisms for the toxicity of fumonisin B 1 in vitro in models in which the proposed biochemical action has been shown to be related to specific molecular events or physiological or toxic effects. Description Model Action Biochemical coovenin lowest concentration Molecular targets Correlated adverse effect Altered lipid metabolism Disruption of sphingolipid metabolism Microsomes: In other primary cultures, sphingolipid-dependent growth inhibition, apoptosis, and functional effects have been found; e.
Decreased glycosphingolipid-dependent cell adhesion, growth, altered cell morphology, or differentiation, and altered vitamin transport Disruption of fatty acid and phospholipid metabolism Primary cultures: Rat hepatocytes Impaired N-6 fatty acid metabolism, covdnin metabolism, and ceramide synthase inhibition Decreased biosynthesis of neutral lipids, triglycerides, and cholesterol; increased phosphatidylcholine and ethanolamine, decreased sphingomyelin, increased free sphinganine.
Altered fatty acid saturation profiles in various lipid pools, in particular accumultion of C In particular, disruption of prostaglandin-mediated responses Increased cytotoxicity and inhibition of epidermal growth factor-induced mitogenesis.
Altered prostaglandin and arachidonic acid-induced cytotoxicity. The structural similarity between sphinganine and fumonisin B 1 led to the hypothesis that this mycotoxin acts by disrupting the metabolism or a function of sphingolipids. There is considerable support for the hypothesis that fumonisin-induced disruption of sphingolipid metabolism is an important event in the cascade of events leading to altered cell growth, differentiation, and cell injury observed both in vitro and in vivo Tables 1—3.
A complete review of the literature on this subject is beyond the scope of this monograph, and the interested reader is referred to WHO a and reviews by Merrill et al. Use of fumonisin B 1 FB 1 in research: Models or processes not summarized previously WHO, a are shown in bold.
Description Model Process affected [lowest fumonisin concentration] Correlated effects and associated molecular events Inhibition of ceramide- or glucosylceramide-induced apoptotic or oncotic cell death Primary cultures: Hen granulosa; rat pancreas, hippocampal neurons; bovine cerebral endothelial, aortic endothelial Inhibition of free fatty acid-induced DNA fragmentation, TNF- alpha -cycloheximide-induced cell death, direct DNA damage-induced apoptosis, glucocerebrosidase-induced apoptosis [0.
Human peripheral T cells; frog oocytes Inhibition of Fas CD95 -induced proliferation, induction of oocyte covenib [0. Mouse macrophage Inhibition of arachadonic 997 release [0. Fumonisin B 1 strongly inhibited the acylation of sphinganine and sphingosine in all cell lines and all animals, plants, and fungi in which it has been tested. Ceramide synthase recognizes both the amino group sphingoid-binding domain and the tricarboxylic acid side-chains fatty acyl-coenzyme A domain of fumonisin B 1.
While removal of the tricarboxylic acid side-chains reduces the ability of fumonisin B 1 to inhibit ceramide synthase, N -acetylation completely abolishes the inhibitory activity Norred et al. Complete coveni of ceramide synthase by fumonisins causes a rapid increase in the intracellular concentration of sphinganine and sometimes of sphingosine, both in vivo and in vitro.