Sphingolipid perturbations as mechanisms for fumonisin carcinogenesis.

Abstract

There is a great deal of evidence that altered sphingolipid metabolism is associated with fumonisin-induced animal diseases including increased apoptotic and oncotic necrosis, and carcinogenesis in rodent liver and kidney. The biochemical consequences of fumonisin disruption of sphingolipid metabolism most likely to alter cell regulation are increased free sphingoid bases and their 1-phosphates, alterations in complex sphingolipids, and decreased ceramide (CER) biosynthesis. Because free sphingoid bases and CER can induce cell death, the fumonisin inhibition of CER synthase can inhibit cell death induced by CER but promote free sphingoid base-induced cell death. Theoretically, at any time the balance between the intracellular concentration of effectors that protect cells from apoptosis (decreased CER, increased sphingosine 1-phosphate) and those that induce apoptosis (increased CER, free sphingoid bases, altered fatty acids) will determine the cellular response. Because the balance between the rates of apoptosis and proliferation is important in tumorigenesis, cells sensitive to the proliferative effect of decreased CER and increased sphingosine 1-phosphate may be selected to survive and proliferate when free sphingoid base concentration is not growth inhibitory. Conversely, when the increase in free sphingoid bases exceeds a cell's ability to convert sphinganine/sphingosine to dihydroceramide/CER or their sphingoid base 1-phosphate, then free sphingoid bases will accumulate. In this case cells that are sensitive to sphingoid base-induced growth arrest will die and insensitive cells will survive. If the cells selected to die are normal phenotypes and the cells selected to survive are abnormal, then cancer risk will increase.

Glucose Reaction with Fumonisin B1Partially Reduces Its Toxicity in Swine

“…Fumonisin B 1 disrupts sphingolipid metabolism by potently inhibiting the enzyme ceramide synthase (sphinganine Nacetyltransferase) in the de noVo biosynthesis pathway of major sphingolipids, thus causing a rapid increase in free sphinganine (Sa), one of the base precursors (11,12). The levels of free Sa and sphingosine (So) in tissues and biological fluids may be compared by constructing a ratio of Sa to So (Sa/So ratio) that is used as an early biomarker of exposure to the mycotoxin (13).…”

“…The levels of free Sa and sphingosine (So) in tissues and biological fluids may be compared by constructing a ratio of Sa to So (Sa/So ratio) that is used as an early biomarker of exposure to the mycotoxin (13). The inhibition of ceramide synthase is also likely to disrupt overall sphingolipid metabolism and, theoretically, sphingolipidmediated regulation of important cell events such as apoptosis and mitosis, which are probably in part responsible for the cytotoxic and carcinogenic properties of the mycotoxin (11,14).…”

An overview of rodent toxicities: liver and kidney effects of fumonisins and Fusarium moniliforme.

“…A more detailed discussion of molecular mechanism is beyond the purpose of this review but can be found elsewhere in this issue (87,(100)(101)(102).…”

Sphingolipid Metabolism: Roles in Signal Transduction and Disruption by Fumonisins

“…Many of the fumonisins, particularly of the B series such as fumonisin B 1 (FB 1 ), are potent inhibitors of ceramide synthase. This disruption of sphingolipid metabolism is a major contributor to the toxicity and carcinogenicity of FB 1 , as described in an accompanying review (1). In this present article we summarize information about basic sphingolipidology that may be useful in understanding fumonisin action.…”

“…Fumonisins are a category of toxic and carcinogeneic mycotoxins that bear a remarkable structural similarity to sphingolipids (1,2). Many of the fumonisins, particularly of the B series such as fumonisin B 1 (FB 1 ), are potent inhibitors of ceramide synthase.…”