Evidence for disruption of sphingolipid metabolism as a contributing factor in the toxicity and carcinogenicity of fumonisins

Abstract

Fumonisins are inhibitors of the biosynthesis of sphingosine and more complex sphingolipids. In eucaryotic cells, fumonisin inhibition of sphingolipid biosynthesis is a result of inhibition of the enzyme ceramide synthase. Large increase in free sphinganine concentration in plant and animal cells are observed within a few hours after exposure to fumonisins and/or Alternaria toxins (AAL-toxins). Some of the sphinganine is metabolized to other bioactive intermediates, and some is released from cells. In animals, free sphinganine accumulates in tissues and quickly appears in blood and urine. Free sphingoid bases are toxic to most cells, and complex sphingolipids are essential for normal cell growth. Fumonisin B1 stimulates sphinganine-dependent DNA synthesis in Swiss 3T3 cells, but is mitoinhibitory in other cell types. In cultured cells the accumulation of bioactive long-chain sphingoid bases and depletion of complex sphingolipids are clearly contributing factors in growth inhibition, increased cell death, and (in Swiss 3T3 cells) mitogenicity of fumonisins. While disruption of sphingolipid metabolism directly affects cells, it may indirectly affect some tissues. For example, fumonisin B1 impairs the barrier function of endothelial cells in vitro. Adverse effects on endothelial cells could indirectly contribute to the neurotoxicity and pulmonary edema caused by fumonisins. It is hypothesized that fumonisin-induced changes in the sphingolipid composition of target tissues could directly or indirectly contribute to all Fusarium moniliforme-associated diseases.

Fumonisins in Maize: Can We Reduce Their Occurrence?

“…A review of sphingolipids is beyond the scope of this paper; we refer the reader to the excellent recent review by Riley et al (46). Sphingolipids are structural components of eukaryotic cell membranes; however, there is increasing evidence that sphingolipids also affect cellular proliferation and differentiation, and that they regulate apoptosis, programmed cell death.…”

Compensatory regeneration as a mechanism for renal tubule carcinogenesis of fumonisin B1 in the F344/N/Nctr BR rat.

“…Inhibition of this enzyme results in increased intracellular sphinganine and decreased intracellular ceramide and complex sphingolipid levels (17,18,22,39). Alterations in these bioactive compounds have been implicated as the mechanism for the induction of apoptosis in cells in vitro (23,37,40).…”

Sphingolipid Metabolism: Roles in Signal Transduction and Disruption by Fumonisins

“…The best characterized among these insults are the fumonisins, which inhibit ceramide synthase, the enzyme that acylates sphingoid bases (sphinganine from de novo synthesis and sphingosine from sphingolipid turnover), as illustrated in Figure 5. Inhibition of ceramide synthase causes sphinganine to accumulate, as shown, and sometimes increases sphingosine; the latter usually occurs later, when there is sufficient cell injury to trigger membrane degradation (1,(28)(29)(30)(31)(32).…”

“…Fumonisins can completely block synthesis of new sphingolipids and deplete the total mass of cellular sphingolipids (1,(28)(29)(30)34,43). However, the magnitude of these responses depends on many factors, such as whether the cells are growing or are confluent (effects are usually greatest in growing cells) (37) and the rate of sphingolipid turnover.…”