Fumonisin B1 - Toxicodynamics

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 Spinganine 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.