MECHANISM OF FUMONISIN TOXICITY AND CARCINOGENESIS

What are the molecular events that fumonisin-induced porcine pulmonary edema syndrome and equine leucoencephalomalacia have in common? Do th ese animal diseases relate mechanistically to fumonisin toxicity in la boratory rats? There is considerable data indicating that disruption o f sphingolipid metabolism plays an important early role in all of thes e diseases. In vitro studies have revealed that fumonisins and structu rally 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 sp hingoid base, sphinganine, in tissues, serum and/or urine. Also, free sphingosine concentration increases, complex sphingolipid concentratio n decreases, and sphingoid base degradation products and other lipid p roducts also increase. It is hypothesized that disruption of sphingoli pid metabolism is an early molecular event in the onset and progressio n of cell injury and the diseases associated with consumption of fumon isins. However, the exact mechanisms responsible for the diseases will not be easily revealed since the role of sphingolipids in cellular re gulation 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 r at liver. It has been hypothesized that hepatotoxicity and effects on hepatocyte proliferation are critical determinants for fumonisin B1 ca ncer initiation and promotion. Alternatively, recent studies have foun d 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 live r cancer in rats.