Mechanism of Fumonisin Toxicity and Carcinogenesis
Abstract:What are the molecular events that fumonisin-induced porcine pulmonary edema syndrome and equine leucoencephalomalacia have in common? Do these animal diseases relate mechanistically to fumonisin toxicity in laboratory rats? There is considerable data indicating that disruption of sphingolipid metabolism plays an important early role in all of these diseases. In vitro studies have revealed that fumonisins and structurally related Alternaria alternata f. sp. lycopersici-toxin (AAL-toxin) are potent inhibitors of the enzyme sphinganine (sphingosine) N-acyl transferase (ceramide synthase). Soon after cultured cells or animals are exposed to fumonisins there is a dramatic increase in the free sphingoid base, sphinganine, in tissues, serum and/or urine. Also, free sphingosine concentration increases, complex sphingolipid concentration decreases, and sphingoid base degradation products and other lipid products also increase. It is hypothesized that disruption of sphingolipid metabolism is an early molecular event in the onset and progression of cell injury and the diseases associated with consumption of fumonisins. However, the exact mechanisms responsible for the diseases will not be easily revealed since the role of sphingolipids in cellular regulation is very complex and not yet fully understood. While fumonisin B1 is non-genotoxic it is a complete carcinogen in rat liver. Recent studies indicate that fumonisins inhibit hepatocyte proliferation in rat liver. It has been hypothesized that hepatotoxicity and effects on hepatocyte proliferation are critical determinants for fumonisin B1 cancer initiation and promotion. Alternatively, recent studies have found that fumonisin B1 has mitogenic activity in cultured fibroblasts. It is conceivable that the mitogenic, cytostatic and cytotoxic potential of fumonisin may all contribute to the animal diseases including liver cancer in rats.
Document Type: Miscellaneous
Affiliations: 1: Toxicology and Mycotoxins Research Unit, U.S. Department of Agriculture/Agricultural Research Service, P.O. Box 5677, Athens, GA 30613 2: PROMEC, Medical Research Council, P.O. Box 19070, Tygerberg 7505, South Africa 3: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322
Publication date: June 1, 1994
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