ELEVATED SPHINGOID BASES AND COMPLEX SPHINGOLIPID DEPLETION AS CONTRIBUTING FACTORS IN FUMONISIN-INDUCED CYTOTOXICITY

Fumonisin B-1 is an inhibitor of ceramide synthase, a key enzyme in de novo sphingolipid biosynthesis and reacylation of free sphingosine, T he purpose of this study was to determine the contribution of increase d intracellular free sphinganine and decreased complex sphingolipids o n cell growth and cell death induced by fumonisin B-1 in pig kidney LL C-PK1 cells, Fumonisin B-1 caused an increase in intracellular free sp hinganine which preceded depletion of complex sphingolipids, inhibitio n of cell growth, and cell death. The effects on cell growth and cell death were well correlated with the increase in free sphingoid bases a nd depletion of complex sphingolipids. Exogenously added sphinganine m imicked the effects of fumonisin, but beta-chloroalanine, an inhibitor of serine palmitoyltransferase which is the first enzyme in de novo s phingolipid biosynthesis, also inhibited cell growth and increased cel l death. When added simultaneously, beta-chloroalanine reduced the fum onisin-induced sphinganine increase by approximately 90%; however, it exacerbated the decrease in more complex sphingolipids. The effects of fumonisin on cell growth and cell death were only partially prevented by beta-chloroalanine (similar to 50 to 60%). The results suggest tha t both the elevation of free sphingoid bases and the decrease in compl ex sphingolipids contribute to the decreased cell growth and cytoletha lity of fumonisin B-1 in pig kidney LLC-PK1 cells. (C) 1996 Academic P ress, Inc.