Fumonisin B1 is the most prevalent member of a family of toxins, known as fumonisins, produced by multiple species of Fusarium molds, such as Fusarium verticillioides, which occur mainly in maize (corn), wheat and other cereals. Fumonisin B1 contamination of maize has been reported worldwide at mg/kg levels. Human exposure occurs at levels of micrograms to milligrams per day and is greatest in regions where maize products are the dietary staple. Fumonisin B1 is hepatotoxic and nephrotoxic in all animal species tested. The earliest histological change to appear in either the liver or kidney of fumonisin-treated animals is increased apoptosis followed by regenerative cell proliferation. While 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. Both of these diseases involve disturbed sphingolipid metabolism and cardiovascular dysfunction.
History In 1970, an outbreak of leukoencephalomalacia in horses in South Africa was associated with the contamination of corn with the fungus Fusarium verticillioides. It is one of the most prevalent seed-borne fungi associated with corn. Another study was done on the possible role of fungal toxins in the etiology of human esophageal cancer in a region in South Africa. The 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. Further outbreaks of leukoencephalomalacia and people in certain regions with high incidence of esophageal cancer led to more research on F. verticillioides. Soon they found experimentally that F. verticillioides caused leukoencephalomalacia in horses and porcine pulmonary edema in pigs. It was found to be highly hepatotoxic and cardiotoxic in rats. In 1984 it was shown that the fungus was hepatocarcinogenic in rats. The chemical nature of the metabolites causing all this had still not been discovered in 1984. After discovery of the carcinogenicity of the fungus, isolation and chemical characterization of the mycotoxins and carcinogens produced by F. verticillioides was urgent. It was not until 1988 that the chemical nature of the carcinogen was unraveled. Fumonisin B1 and fumonisin B2 were isolated from cultures of F. verticillioides at the Programme on Mycotoxins and Experimental Carcinogenesis. The structures were elucidated in collaboration with the Council for Scientific and Industrial Research. Several isomers of fumonisin B1 have been detected in solid rice culture. Now more than 100 different fumonisins are known, the most important ones being fumonisin B1, B2 and B3.
Toxicokinetics Regarding toxicokinetics there is no human data available, but research on animals has been done.
Absorption FB1 is taken orally via food. Overall, FB1 is poorly absorbed, less than 6%. Absorption of orally administered fumonisin B1 (10 mg/kg body weight) to rats is low (3.5% of dose) but rapid (Tmax = 1.02 h). FB1 does not significantly permeate through the human skin and hence has no significant systemic health risk after dermal exposure.
Distribution After absorption, some appears to be retained in liver and kidneys. For 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. Plasma distribution of the absorbed dose conformed to a two-compartment open model and the tissue (liver, kidney) concentration time results were consistent with a one-compartment open model.
Excretion Elimination half-life in rats is 3.15 h for plasma, 4.07 h for liver, and 7.07 h for kidney. However, FB1 is rapidly excreted mostly in its original form. Small amounts are excreted in urine; the most are excreted in feces.
Toxicodynamics Because of their similarity, fumonisins are able to inhibit sphingosine-sphinganin-transferases and ceramide synthases and are therefore competitive inhibitors of sphingolipid biosynthesis and metabolism.
Figure 2 shows the sphingolipid metabolism (schematic) and the inhibition caused by fumonisins. Fumonisin B1 inhibits the enzyme ceramide synthase (sphingosine N-acyltransferase), which acylates sphingoid bases. This blocks the formation of ceramide via two pathways. It inhibits de formation via de novo sphinganine and fatty acyl-CoA and via sphingosine produced by the breakdown of ceramide by ceramidase. The inhibition results in increased concentrations of sphinganine, sphingosine and their 1-phosphate metabolites and in decreased concentrations of complex sphingolipids. The 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. Also, these sphingoid bases induce apoptosis. Increased apoptosis seems to play an important role in the toxic effects including tumor induction. However, 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. The balance between the intracellular concentration of compounds that inhibit apoptosis and those that induce apoptosis will determine the cellular response. Also, the decreased concentrations of complex sphingolipids appear to play a role in the abnormal behavior and altered morphology of the affected cells.
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![Fumonisin B1: Figure 2: Sphingolipid metabolism showing the inhibition of ceramide synthase (x) by fumonisins and the changed concentrations of other compounds caused by this inhibition.[12]](https://upload.wikimedia.org/wikipedia/commons/thumb/1/1f/Sphingolipid_metabolism.png/500px-Sphingolipid_metabolism.png?utm_source=en.wikipedia.org&utm_campaign=parser&utm_content=thumbnail)
