{"history":[],"article":{"id":"f315e462-a59f-4381-842a-c98c52459288","title":"Fumonisin B1","slug":"fumonisin-b1","content":":::summary\n:::\n\n# \n**Fumonisin B1** is the most prevalent member of a family of toxins, known as [fumonisins](https://bliptext.com/articles/fumonisin), produced by multiple species of [Fusarium](https://bliptext.com/articles/fusarium) [molds](https://bliptext.com/articles/mold-fungus), such as [Fusarium](https://bliptext.com/articles/fusarium) verticillioides, which occur mainly in maize (corn), wheat and other cereals.\nFumonisin B1 contamination of maize has been reported worldwide at mg/kg levels.\nHuman exposure occurs at levels of micrograms to milligrams per day and is greatest in regions where maize products are the dietary staple.\nFumonisin B1 is [hepatotoxic](https://bliptext.com/articles/hepatotoxic) and [nephrotoxic](https://bliptext.com/articles/nephrotoxic) in all animal species tested.\nThe earliest histological change to appear in either the liver or kidney of fumonisin-treated animals is increased apoptosis followed by regenerative cell proliferation.\nWhile the acute toxicity of fumonisin is low, it is the known cause of two diseases which occur in domestic animals with rapid onset: equine leukoencephalomalacia and porcine pulmonary oedema syndrome.\nBoth of these diseases involve disturbed sphingolipid metabolism and cardiovascular dysfunction.\n\n# History\nIn 1970, an outbreak of [leukoencephalomalacia](https://bliptext.com/articles/leukoencephalomalacia) in horses in South Africa was associated with the contamination of corn with the fungus [Fusarium verticillioides](https://bliptext.com/articles/fusarium-verticillioides).\nIt is one of the most prevalent seed-borne fungi associated with corn.\nAnother study was done on the possible role of fungal toxins in the [etiology](https://bliptext.com/articles/etiology) of human [esophageal cancer](https://bliptext.com/articles/esophageal-cancer) in a region in South Africa.\nThe diet of the people living in this area was homegrown corn and F. verticillioides was the most prevalent fungus in the corn consumed by the people with high incidence of esophageal cancer.\nFurther outbreaks of leukoencephalomalacia and people in certain regions with high incidence of esophageal cancer led to more research on F. verticillioides.\nSoon they found experimentally that F. verticillioides caused leukoencephalomalacia in horses and porcine [pulmonary edema](https://bliptext.com/articles/pulmonary-edema) in pigs.\nIt was found to be highly hepatotoxic and cardiotoxic in rats.\nIn 1984 it was shown that the fungus was hepatocarcinogenic in rats.\nThe chemical nature of the metabolites causing all this had still not been discovered in 1984.\nAfter discovery of the carcinogenicity of the fungus, isolation and chemical characterization of the mycotoxins and carcinogens produced by F. verticillioides was urgent.\nIt wasn't until 1988 that the chemical nature of the carcinogen was unraveled.\nFumonisin B1 and fumonisin B2 were isolated from cultures of F. verticillioides at the Programme on Mycotoxins and Experimental Carcinogenesis.\nThe structures were elucidated in collaboration with the Council for Scientific and Industrial Research.\nSeveral isomers of fumonisin B1 have been detected in solid rice culture.\nNow more than 100 different fumonisins are known, the most important ones being fumonisin B1, B2 and B3.\n# [Figure 1: Fusarium ear rot, caused by the fungi Fusarium verticillioides and F. proliferatum, may typically be a more common ear rot of corn.\nSource: UIUC available at: http://www.extension.umn.edu/cropenews/2007/07MNCN42.html | upload.wikimedia.org/wikipedia/commons/0/0d/Corn///mold.jpg]\n\n# Toxicokinetics\nRegarding toxicokinetics there is no human data available, but research on animals has been done.\n\n## Absorption\nFB1 is taken orally via food.\nOverall, FB1 is poorly absorbed, less than 6%.\nAbsorption of orally administered fumonisin B1 (10 mg/kg body weight) to rats is low (3.5% of dose) but rapid (Tmax = 1.02 h).\nFB1 does not significantly permeate through the human skin and hence has no significant systemic health risk after dermal exposure.\n\n## Distribution\nAfter absorption, some appears to be retained in liver and kidneys.\nFor rats that were fed diets containing fumonisins for several weeks, the concentrations of the fumonisins in the kidneys were approximately 10-fold higher than in the liver.\nPlasma distribution of the absorbed dose conformed to a [two-compartment open model](https://bliptext.com/articles/multi-compartment-model) and the tissue (liver, kidney) concentration time results were consistent with a [one-compartment open model](https://bliptext.com/articles/one-compartment-kinetics).\n\n## Excretion\nElimination half-life in rats is 3.15 h for plasma, 4.07 h for liver, and 7.07 h for kidney.\nHowever, FB1 is rapidly excreted mostly in its original form.\nSmall amounts are excreted in urine; the most are excreted in feces.\n\n# Toxicodynamics\nBecause of their similarity, fumonisins are able to inhibit [sphingosine](https://bliptext.com/articles/sphingosine)-sphinganin-transferases and [ceramide](https://bliptext.com/articles/ceramide) [synthases](https://bliptext.com/articles/synthase) and are therefore [competitive](https://bliptext.com/articles/competitive-inhibition) inhibitors of [sphingolipid](https://bliptext.com/articles/sphingolipid) biosynthesis and metabolism.\nFigure 2 shows the sphingolipid metabolism (schematic) and the inhibition caused by fumonisins.\nFumonisin B1 inhibits the enzyme ceramide synthase (sphingosine N-acyltransferase), which acylates sphingoid bases.\nThis blocks the formation of ceramide via two pathways.\nIt inhibits de formation via de novo sphinganine and fatty [acyl-CoA](https://bliptext.com/articles/acyl-coa) and via sphingosine produced by the breakdown of ceramide by ceramidase.\nThe inhibition results in increased concentrations of sphinganine, sphingosine and their 1-phosphate metabolites and in decreased concentrations of complex sphingolipids.\nThe accumulation of sphinganine and sphingosine is a primary cause of the toxicity of fumonisin B1 Sphinganine and sphingosine are cytotoxic, and have growth inhibitory effects.\nAlso, these sphingoid bases induce apoptosis.\nIncreased apoptosis seems to play an important role in the toxic effects including tumor induction.\nHowever, it should be mentioned that the reduced concentration of ceramide and the increased concentration of sphingosine-1-phosphate (as a result of FB1 intake) cause an inhibition of apoptosis and promote mitosis and regeneration.\nThe balance between the intracellular concentration of compounds that inhibit apoptosis and those that induce apoptosis will determine the cellular response.\nAlso, the decreased concentrations of complex sphingolipids appear to play a role in the abnormal behavior and altered morphology of the affected cells.\n# [Figure 2: Sphingolipid metabolism showing the inhibition of ceramide synthase (x) by fumonisins and the changed concentrations of other compounds caused by this inhibition. | upload.wikimedia.org/wikipedia/commons/1/1f/Sphingolipid///metabolism.png]\n\n# Mechanism of action\nThe proposed mechanism of action is depicted in figure 3.\nFumonisin B1 occupies the space and electrostatic interactions of both sphinganine (or sphingosine) and fatty acyl-CoA in ceramide synthase.\nThe part of FB1 that has structural similarity with sphingoid bases (the aminopentol part) may interact with the sphinganine binding site, whereas the negatively charged tricarbyllic acid groups may interact with the fatty acyl-CoA binding site.\nBecause FB1 also occupies the fatty acyl-CoA space, it isn't acylated, since acyl-CoA is necessary for the acylation; FB1 only inhibits ceramide synthase.\nHowever, when the tricarbillic acid groups are removed from FB1 by hydrolysis, the resulting product (aminopentol, AP1) doesn't only act as an inhibitor, but also as a substrate for ceramide synthase; aminopentol is acylated by ceramide synthase to form N-palmitoyl-AP1.\nThis supports the suggestion that the aminopentol part of FB1 occupies the space of sphinganine in the enzyme.\nN-palmitoyl-AP1 is an even more potent inhibitor of ceramide synthase and may therefore play a role in the toxicity of nixtamalized fumonisins.\n# [Figure 3: Proposed mechanism of action of ceramide synthase inhibition by FB1; FB1 mimics regions of the sphingoid base and the fatty acyl-CoA substrates. (Merrill et al., 2001) | upload.wikimedia.org/wikipedia/commons/8/8c/Ceramidesynthasefb1.png]\n\n# Toxic effects\nThe risks of fumonisin B1 have been evaluated by The World Health Organization's International Programme on Chemical Safety and the Scientific Committee on Food of the European Commission.\nThey determined a tolerable daily intake for FB₁, FB₂, FB₃, alone or in combination of 2 μg/kg body weight.\nUntil now, nothing about the kinetics and metabolism of fumonisin B₁ in humans have been reported.\nOn other animals much research has been done, but it might not be comparable to humans.\nIn mice the elimination of FB₁ is very rapid, but in humans it could be much slower considering their body weight.\nThere are several possible pathways that cause toxic effects of Fumonisin B₁.\nMost toxic effects are due to altered sphingolipid metabolism by inhibition of ceramide synthase.\nProduction of reactive oxygen species could occur.\nThis increases oxidative stress and induce lipid peroxidation and could damage cells.\nIn agreement with this some studies showed decreased levels of glutathione in liver, but other studies showed even elevated levels of glutathione.\nCytotoxic effects have also been reported.\nAnother effect of exposure to FB₁ is apoptosis.\nThis has been observed in a number of different cells and tissues.\nInhibition of ceramide synthase is not responsible for this effect.\nThe main factors could be DNA fragmentation and caspase-3 activation.\nFB₁ has also immunotoxic effects, but much more research is necessary to get a clear overview of the effects on the immune system.\n\n## Toxic effects in humans\n\n### Neural tube defects\nNeural tube defect are abnormalities of the brain and spinal cord in the embryo resulting from failure of the neural tube to close.\nEpidemiological studies and clinical trials have pointed out folate deficiency as a major risk factor for neural tube defects.\nFB₁ disrupts sphingolipid metabolism and therefore this could affect folate uptake and cause neural tube defects.\nIn 1990 and 1991 a sudden outbreak of neural tube defects occurred along the Texas-Mexico border.\nIt is believed that this outbreak might have been due to high levels of FB₁ that were observed in corn during previous years.\nRegions in China and South Africa with high corn consumption also have a high prevalence of neural tube defects.\n\n### Esophageal cancer\nIt is thought that there is a relationship between the occurrence of F. verticillioides and human esophageal cancer.\nA low socioeconomic status and a less varied diet, that mainly consists of corn and wheat, is associated with the appearance of esophageal cancer.\nThis derives from epidemiologic studies in various countries.\nOther studies show that higher concentrations of FB₁, FB₂ and F. verticillioides are present in corn growing in regions with a high percentage of esophageal cancer.\nThis in contrast with regions with low levels of F. verticillioides, FB₁ and FB₂ in corn.\nOn top of this it seems that people with a high corn intake are at higher risk to develop esophageal cancer than people with low corn intake.\nThis is observed by people in regions in Italy, Iran, Kenia, Zimbabwe, United States and Brazil with high incidence of esophageal cancer.\nAnother study on the relationship between sphingolipid levels and cancer incidence didn't show any significant relationship between serum sphingolipids and risk of esophageal cancer.\nThis is quite remarkable, because elevated levels of sphingolipids sphinganine and sphingosine are believed to be biomarkers for exposure of FB₁.\n\n### Acute mycotoxicosis\nAcute mycotoxicosis is food poisoning by food products contaminated by fungi.\nIn 1995 an outbreak of disease characterized by diarrhea and abdominal pain occurred in 27 villages in India.\nThis was the result of consumption of moldy sorghum and corn due to rain damage.\nThis outbreak was studied and the mycotoxicosis was connected to consumption of unleavened bread.\nCorn and sorghum samples were collected from the households and examined.\nThe corn and sorghum were contaminated by Fusarium and Aspergillus and contained high levels of FB₁ compared with samples of unaffected households.\n\n## Toxic effects in animals\nMuch research has been done on toxic effects of FB₁ in animals.\nIn vivo studies indicate that liver and kidneys are the main target organs.\nFumonisins are poorly absorbed, rapidly eliminated and not metabolized in animals.\nIn pigs and rats there is a wide distribution of FB₁ and small amounts have been found to accumulate only in liver and kidneys.\nIn [vervet monkeys](https://bliptext.com/articles/vervet-monkey), some FB₁ is partially hydrolyzed in the gut.\n\n### Carcinogenic effects\nIn rats and mice that were exposed to FB₁ tumor formation occurred.\nSeveral studies on this subject have been done.\nDepending on the strain of mice being used different carcinomas were shown.\nFB₁ is shown to be nongenotoxic.\nTherefore, the mechanisms responsible for cancer development should lie elsewhere.\nImportant mechanisms for cancer development due to fumonisin B₁ could be oxidative damage (production of reactive oxygen species) and lipid peroxidation.\nHepatic and renal tumors could also be due to apoptosis by FB₁.\nAs a response to this there could be continuous regeneration of cells, causing cancer.\nIt seems to be that disrupted sphingolipid metabolism is the causative factor for FB₁-induced carcinogenicity, as is the case with the toxic effects.\nBased on all these animal studies FB₁ is classified by The International Agency for Research on Cancer (IARC) as possibly carcinogenic to humans (Group 2B).\n\n### Porcine pulmonary edema\nPorcine pulmonary edema due to FB₁ is intensively studied after the first report in 1981 of swine with pulmonary edema after exposure to corn contaminated with F. verticillioides.\nAlteration in sphingolipid biosynthesis are reported, especially in lung, heart, kidney and liver tissue.\nLethal pulmonary edema was developed within 4–7 days after exposure to feed with concentrations of FB₁ >16 mg/kg body weight (>92 parts per million).\nDoses of 10 parts per million caused a milder form of pulmonary edema.\n\n### Equine leukoencephalomalacia\nLeukoencephalomalacia is a neurotoxic disease of horses.\nOutbreaks of this disease in the 20th century resulted in a number of studies.\nApparently FB₁ was the cause for this disease.\nThere were shown elevated levels of serum enzyme levels that indicate liver damage.\nThey were normally observed by an elevation of the sphinganine/sphingosine ratio.\nFB₁ possibly induces cardiovascular function, because of the elevated sphinganine/sphingosine ratio.\nThis could be one of the main factors that causes leukoencephalomalacia.\n\n## Toxicity in laboratory animals\nEffects of feeding rats with FB₁ for up to 90 days were usually nephrotoxicity.\nBetween different strains of rats, sensitivity to FB₁ varied.\nIn the kidneys the main effect was apoptosis.\nAlso tubular atrophy and regeneration as well as decreased kidney weight was reported.\nHistopathologic effects on rat liver were reported after both short- and long-term exposure.\nThe main cause was apoptosis.\nMice don't seem to be very sensitive to nephrotoxic effects in comparison with rats.\nIn mouse kidneys little histological changes were seen by high dose exposure.\nThe liver was also the main target organ in mice.\nPathology is similar as in rats, with apoptosis and hepatocellular hyperplasia.\nFumonisin B₁ is possibly embryotoxic if the dose is maternally toxic.\nA number of studies on genotoxicity indicated no mutagenetic effects.\nAlthough fumonisin could damage DNA directly by production of reactive oxygen species.\nMouse embryos were exposed to FB₁ and they showed inhibited sphingolipid synthesis and growth.\nIt caused neural tube defects.\nFolic acid uptake was dramatically inhibited.\nTreatment after exposure with folic acid reduced neural tube defects by 50–65%.\n\n# Tolerable daily intake\nThe risks of fumonisin B1 have been evaluated by The World Health Organization's International Programme on Chemical Safety and the Scientific Committee on Food of the European Commission.\nThey determined a tolerable daily intake for FB1, FB2, FB3, alone or in combination of 2 μg/kg body weight.\n\n# Detoxification\nThe inhibition of ceramide synthase by FB1 is thought to be reversible, since the binding is formed by noncovalent interactions.\nFactors that will probably induce this reversibility are reduction of cellular FB1-concentration and increasing of cellular concentrations of the substrates for ceramide synthase.\nAlso, the rate of removal of the accumulated sphinganine and sphingosine will affect the detoxification.\nThe information on metabolism and [biotransformation](https://bliptext.com/articles/biotransformation) of FB1 is very sparse.\nHowever, metabolism most likely occurs in the gut since partially hydrolysed and fully hydrolysed FB1 were recovered in faeces but not in bile of vervet monkeys.\nBioavailability of FB1 can be reduced by treating fumonisin-contaminated corn with glucomannans extracted from the cell wall of the yeast Saccharomyces cerevisiae.\nThese polysaccharides are able to bind certain mycotoxins and have a 67% binding capacity for fumonisins.","current_revision":null,"created_by":"kACnuQmH5k9Nr5VNVEpVeg7XpvUmMctD","created_at":"2025-01-25T21:40:52.180Z","updated_at":"2025-01-25T21:40:52.180Z","search_vector":"'b1':2 'fumonisin':1","search_content":" \n \n\n# \n**Fumonisin B1** is the most prevalent member of a family of toxins, known as [fumonisins](https://bliptext.com/articles/fumonisin), produced by multiple species of [Fusarium](https://bliptext.com/articles/fusarium) [molds](https://bliptext.com/articles/mold-fungus), such as [Fusarium](https://bliptext.com/articles/fusarium) verticillioides, which occur mainly in maize (corn), wheat and other cereals.\nFumonisin B1 contamination of maize has been reported worldwide at mg/kg levels.\nHuman exposure occurs at levels of micrograms to milligrams per day and is greatest in regions where maize products are the dietary staple.\nFumonisin B1 is [hepatotoxic](https://bliptext.com/articles/hepatotoxic) and [nephrotoxic](https://bliptext.com/articles/nephrotoxic) in all animal species tested.\nThe earliest histological change to appear in either the liver or kidney of fumonisin-treated animals is increased apoptosis followed by regenerative cell proliferation.\nWhile the acute toxicity of fumonisin is low, it is the known cause of two diseases which occur in domestic animals with rapid onset: equine leukoencephalomalacia and porcine pulmonary oedema syndrome.\nBoth of these diseases involve disturbed sphingolipid metabolism and cardiovascular dysfunction.\n\n# History\nIn 1970, an outbreak of [leukoencephalomalacia](https://bliptext.com/articles/leukoencephalomalacia) in horses in South Africa was associated with the contamination of corn with the fungus [Fusarium verticillioides](https://bliptext.com/articles/fusarium-verticillioides).\nIt is one of the most prevalent seed-borne fungi associated with corn.\nAnother study was done on the possible role of fungal toxins in the [etiology](https://bliptext.com/articles/etiology) of human [esophageal cancer](https://bliptext.com/articles/esophageal-cancer) in a region in South Africa.\nThe diet of the people living in this area was homegrown corn and F. verticillioides was the most prevalent fungus in the corn consumed by the people with high incidence of esophageal cancer.\nFurther outbreaks of leukoencephalomalacia and people in certain regions with high incidence of esophageal cancer led to more research on F. verticillioides.\nSoon they found experimentally that F. verticillioides caused leukoencephalomalacia in horses and porcine [pulmonary edema](https://bliptext.com/articles/pulmonary-edema) in pigs.\nIt was found to be highly hepatotoxic and cardiotoxic in rats.\nIn 1984 it was shown that the fungus was hepatocarcinogenic in rats.\nThe chemical nature of the metabolites causing all this had still not been discovered in 1984.\nAfter discovery of the carcinogenicity of the fungus, isolation and chemical characterization of the mycotoxins and carcinogens produced by F. verticillioides was urgent.\nIt wasn't until 1988 that the chemical nature of the carcinogen was unraveled.\nFumonisin B1 and fumonisin B2 were isolated from cultures of F. verticillioides at the Programme on Mycotoxins and Experimental Carcinogenesis.\nThe structures were elucidated in collaboration with the Council for Scientific and Industrial Research.\nSeveral isomers of fumonisin B1 have been detected in solid rice culture.\nNow more than 100 different fumonisins are known, the most important ones being fumonisin B1, B2 and B3.\n# [Figure 1: Fusarium ear rot, caused by the fungi Fusarium verticillioides and F. proliferatum, may typically be a more common ear rot of corn.\nSource: UIUC available at: http://www.extension.umn.edu/cropenews/2007/07MNCN42.html | upload.wikimedia.org/wikipedia/commons/0/0d/Corn///mold.jpg]\n\n# Toxicokinetics\nRegarding toxicokinetics there is no human data available, but research on animals has been done.\n\n## Absorption\nFB1 is taken orally via food.\nOverall, FB1 is poorly absorbed, less than 6%.\nAbsorption of orally administered fumonisin B1 (10 mg/kg body weight) to rats is low (3.5% of dose) but rapid (Tmax = 1.02 h).\nFB1 does not significantly permeate through the human skin and hence has no significant systemic health risk after dermal exposure.\n\n## Distribution\nAfter absorption, some appears to be retained in liver and kidneys.\nFor rats that were fed diets containing fumonisins for several weeks, the concentrations of the fumonisins in the kidneys were approximately 10-fold higher than in the liver.\nPlasma distribution of the absorbed dose conformed to a [two-compartment open model](https://bliptext.com/articles/multi-compartment-model) and the tissue (liver, kidney) concentration time results were consistent with a [one-compartment open model](https://bliptext.com/articles/one-compartment-kinetics).\n\n## Excretion\nElimination half-life in rats is 3.15 h for plasma, 4.07 h for liver, and 7.07 h for kidney.\nHowever, FB1 is rapidly excreted mostly in its original form.\nSmall amounts are excreted in urine; the most are excreted in feces.\n\n# Toxicodynamics\nBecause of their similarity, fumonisins are able to inhibit [sphingosine](https://bliptext.com/articles/sphingosine)-sphinganin-transferases and [ceramide](https://bliptext.com/articles/ceramide) [synthases](https://bliptext.com/articles/synthase) and are therefore [competitive](https://bliptext.com/articles/competitive-inhibition) inhibitors of [sphingolipid](https://bliptext.com/articles/sphingolipid) biosynthesis and metabolism.\nFigure 2 shows the sphingolipid metabolism (schematic) and the inhibition caused by fumonisins.\nFumonisin B1 inhibits the enzyme ceramide synthase (sphingosine N-acyltransferase), which acylates sphingoid bases.\nThis blocks the formation of ceramide via two pathways.\nIt inhibits de formation via de novo sphinganine and fatty [acyl-CoA](https://bliptext.com/articles/acyl-coa) and via sphingosine produced by the breakdown of ceramide by ceramidase.\nThe inhibition results in increased concentrations of sphinganine, sphingosine and their 1-phosphate metabolites and in decreased concentrations of complex sphingolipids.\nThe accumulation of sphinganine and sphingosine is a primary cause of the toxicity of fumonisin B1 Sphinganine and sphingosine are cytotoxic, and have growth inhibitory effects.\nAlso, these sphingoid bases induce apoptosis.\nIncreased apoptosis seems to play an important role in the toxic effects including tumor induction.\nHowever, it should be mentioned that the reduced concentration of ceramide and the increased concentration of sphingosine-1-phosphate (as a result of FB1 intake) cause an inhibition of apoptosis and promote mitosis and regeneration.\nThe balance between the intracellular concentration of compounds that inhibit apoptosis and those that induce apoptosis will determine the cellular response.\nAlso, the decreased concentrations of complex sphingolipids appear to play a role in the abnormal behavior and altered morphology of the affected cells.\n# [Figure 2: Sphingolipid metabolism showing the inhibition of ceramide synthase (x) by fumonisins and the changed concentrations of other compounds caused by this inhibition. | upload.wikimedia.org/wikipedia/commons/1/1f/Sphingolipid///metabolism.png]\n\n# Mechanism of action\nThe proposed mechanism of action is depicted in figure 3.\nFumonisin B1 occupies the space and electrostatic interactions of both sphinganine (or sphingosine) and fatty acyl-CoA in ceramide synthase.\nThe part of FB1 that has structural similarity with sphingoid bases (the aminopentol part) may interact with the sphinganine binding site, whereas the negatively charged tricarbyllic acid groups may interact with the fatty acyl-CoA binding site.\nBecause FB1 also occupies the fatty acyl-CoA space, it isn't acylated, since acyl-CoA is necessary for the acylation; FB1 only inhibits ceramide synthase.\nHowever, when the tricarbillic acid groups are removed from FB1 by hydrolysis, the resulting product (aminopentol, AP1) doesn't only act as an inhibitor, but also as a substrate for ceramide synthase; aminopentol is acylated by ceramide synthase to form N-palmitoyl-AP1.\nThis supports the suggestion that the aminopentol part of FB1 occupies the space of sphinganine in the enzyme.\nN-palmitoyl-AP1 is an even more potent inhibitor of ceramide synthase and may therefore play a role in the toxicity of nixtamalized fumonisins.\n# [Figure 3: Proposed mechanism of action of ceramide synthase inhibition by FB1; FB1 mimics regions of the sphingoid base and the fatty acyl-CoA substrates. (Merrill et al., 2001) | upload.wikimedia.org/wikipedia/commons/8/8c/Ceramidesynthasefb1.png]\n\n# Toxic effects\nThe risks of fumonisin B1 have been evaluated by The World Health Organization's International Programme on Chemical Safety and the Scientific Committee on Food of the European Commission.\nThey determined a tolerable daily intake for FB 1 , FB 2 , FB 3 , alone or in combination of 2 μg/kg body weight.\nUntil now, nothing about the kinetics and metabolism of fumonisin B 1 in humans have been reported.\nOn other animals much research has been done, but it might not be comparable to humans.\nIn mice the elimination of FB 1 is very rapid, but in humans it could be much slower considering their body weight.\nThere are several possible pathways that cause toxic effects of Fumonisin B 1 .\nMost toxic effects are due to altered sphingolipid metabolism by inhibition of ceramide synthase.\nProduction of reactive oxygen species could occur.\nThis increases oxidative stress and induce lipid peroxidation and could damage cells.\nIn agreement with this some studies showed decreased levels of glutathione in liver, but other studies showed even elevated levels of glutathione.\nCytotoxic effects have also been reported.\nAnother effect of exposure to FB 1 is apoptosis.\nThis has been observed in a number of different cells and tissues.\nInhibition of ceramide synthase is not responsible for this effect.\nThe main factors could be DNA fragmentation and caspase-3 activation.\nFB 1 has also immunotoxic effects, but much more research is necessary to get a clear overview of the effects on the immune system.\n\n## Toxic effects in humans\n\n### Neural tube defects\nNeural tube defect are abnormalities of the brain and spinal cord in the embryo resulting from failure of the neural tube to close.\nEpidemiological studies and clinical trials have pointed out folate deficiency as a major risk factor for neural tube defects.\nFB 1 disrupts sphingolipid metabolism and therefore this could affect folate uptake and cause neural tube defects.\nIn 1990 and 1991 a sudden outbreak of neural tube defects occurred along the Texas-Mexico border.\nIt is believed that this outbreak might have been due to high levels of FB 1 that were observed in corn during previous years.\nRegions in China and South Africa with high corn consumption also have a high prevalence of neural tube defects.\n\n### Esophageal cancer\nIt is thought that there is a relationship between the occurrence of F. verticillioides and human esophageal cancer.\nA low socioeconomic status and a less varied diet, that mainly consists of corn and wheat, is associated with the appearance of esophageal cancer.\nThis derives from epidemiologic studies in various countries.\nOther studies show that higher concentrations of FB 1 , FB 2 and F. verticillioides are present in corn growing in regions with a high percentage of esophageal cancer.\nThis in contrast with regions with low levels of F. verticillioides, FB 1 and FB 2 in corn.\nOn top of this it seems that people with a high corn intake are at higher risk to develop esophageal cancer than people with low corn intake.\nThis is observed by people in regions in Italy, Iran, Kenia, Zimbabwe, United States and Brazil with high incidence of esophageal cancer.\nAnother study on the relationship between sphingolipid levels and cancer incidence didn't show any significant relationship between serum sphingolipids and risk of esophageal cancer.\nThis is quite remarkable, because elevated levels of sphingolipids sphinganine and sphingosine are believed to be biomarkers for exposure of FB 1 .\n\n### Acute mycotoxicosis\nAcute mycotoxicosis is food poisoning by food products contaminated by fungi.\nIn 1995 an outbreak of disease characterized by diarrhea and abdominal pain occurred in 27 villages in India.\nThis was the result of consumption of moldy sorghum and corn due to rain damage.\nThis outbreak was studied and the mycotoxicosis was connected to consumption of unleavened bread.\nCorn and sorghum samples were collected from the households and examined.\nThe corn and sorghum were contaminated by Fusarium and Aspergillus and contained high levels of FB 1 compared with samples of unaffected households.\n\n## Toxic effects in animals\nMuch research has been done on toxic effects of FB 1 in animals.\nIn vivo studies indicate that liver and kidneys are the main target organs.\nFumonisins are poorly absorbed, rapidly eliminated and not metabolized in animals.\nIn pigs and rats there is a wide distribution of FB 1 and small amounts have been found to accumulate only in liver and kidneys.\nIn [vervet monkeys](https://bliptext.com/articles/vervet-monkey), some FB 1 is partially hydrolyzed in the gut.\n\n### Carcinogenic effects\nIn rats and mice that were exposed to FB 1 tumor formation occurred.\nSeveral studies on this subject have been done.\nDepending on the strain of mice being used different carcinomas were shown.\nFB 1 is shown to be nongenotoxic.\nTherefore, the mechanisms responsible for cancer development should lie elsewhere.\nImportant mechanisms for cancer development due to fumonisin B 1 could be oxidative damage (production of reactive oxygen species) and lipid peroxidation.\nHepatic and renal tumors could also be due to apoptosis by FB 1 .\nAs a response to this there could be continuous regeneration of cells, causing cancer.\nIt seems to be that disrupted sphingolipid metabolism is the causative factor for FB 1 -induced carcinogenicity, as is the case with the toxic effects.\nBased on all these animal studies FB 1 is classified by The International Agency for Research on Cancer (IARC) as possibly carcinogenic to humans (Group 2B).\n\n### Porcine pulmonary edema\nPorcine pulmonary edema due to FB 1 is intensively studied after the first report in 1981 of swine with pulmonary edema after exposure to corn contaminated with F. verticillioides.\nAlteration in sphingolipid biosynthesis are reported, especially in lung, heart, kidney and liver tissue.\nLethal pulmonary edema was developed within 4–7 days after exposure to feed with concentrations of FB 1 >16 mg/kg body weight (>92 parts per million).\nDoses of 10 parts per million caused a milder form of pulmonary edema.\n\n### Equine leukoencephalomalacia\nLeukoencephalomalacia is a neurotoxic disease of horses.\nOutbreaks of this disease in the 20th century resulted in a number of studies.\nApparently FB 1 was the cause for this disease.\nThere were shown elevated levels of serum enzyme levels that indicate liver damage.\nThey were normally observed by an elevation of the sphinganine/sphingosine ratio.\nFB 1 possibly induces cardiovascular function, because of the elevated sphinganine/sphingosine ratio.\nThis could be one of the main factors that causes leukoencephalomalacia.\n\n## Toxicity in laboratory animals\nEffects of feeding rats with FB 1 for up to 90 days were usually nephrotoxicity.\nBetween different strains of rats, sensitivity to FB 1 varied.\nIn the kidneys the main effect was apoptosis.\nAlso tubular atrophy and regeneration as well as decreased kidney weight was reported.\nHistopathologic effects on rat liver were reported after both short- and long-term exposure.\nThe main cause was apoptosis.\nMice don't seem to be very sensitive to nephrotoxic effects in comparison with rats.\nIn mouse kidneys little histological changes were seen by high dose exposure.\nThe liver was also the main target organ in mice.\nPathology is similar as in rats, with apoptosis and hepatocellular hyperplasia.\nFumonisin B 1 is possibly embryotoxic if the dose is maternally toxic.\nA number of studies on genotoxicity indicated no mutagenetic effects.\nAlthough fumonisin could damage DNA directly by production of reactive oxygen species.\nMouse embryos were exposed to FB 1 and they showed inhibited sphingolipid synthesis and growth.\nIt caused neural tube defects.\nFolic acid uptake was dramatically inhibited.\nTreatment after exposure with folic acid reduced neural tube defects by 50–65%.\n\n# Tolerable daily intake\nThe risks of fumonisin B1 have been evaluated by The World Health Organization's International Programme on Chemical Safety and the Scientific Committee on Food of the European Commission.\nThey determined a tolerable daily intake for FB1, FB2, FB3, alone or in combination of 2 μg/kg body weight.\n\n# Detoxification\nThe inhibition of ceramide synthase by FB1 is thought to be reversible, since the binding is formed by noncovalent interactions.\nFactors that will probably induce this reversibility are reduction of cellular FB1-concentration and increasing of cellular concentrations of the substrates for ceramide synthase.\nAlso, the rate of removal of the accumulated sphinganine and sphingosine will affect the detoxification.\nThe information on metabolism and [biotransformation](https://bliptext.com/articles/biotransformation) of FB1 is very sparse.\nHowever, metabolism most likely occurs in the gut since partially hydrolysed and fully hydrolysed FB1 were recovered in faeces but not in bile of vervet monkeys.\nBioavailability of FB1 can be reduced by treating fumonisin-contaminated corn with glucomannans extracted from the cell wall of the yeast Saccharomyces cerevisiae.\nThese polysaccharides are able to bind certain mycotoxins and have a 67% binding capacity for fumonisins.","revisionCount":0},"hasMore":false,"nextCursor":null}