|Yoo, Hwan-Soo - PHARM-TOX, U GEORGIA|
Submitted to: Journal of Toxicology and Applied Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 26, 1996
Publication Date: N/A
Interpretive Summary: Fumonisins are poisons produced by molds often found on corn. Occasionally these molds produce the poisonous fumonisins in amounts that cause a brain disease in horses and a lung disease in pigs. Liver and kidney disease occurs in farm and laboratory animals which are fed corn-based feeds containing fumonisins. They are also suspected of causing human disease in countries where corn is a staple. Very little is known about how the fumonisins cause the animal diseases. Recent work in our laboratory has shown that the fumonisins alter the way a poorly understood group of fats called sphingolipids (named after the Sphinx) are metabolized. This finding has led us to propose that alteration in fat metabolism is the basis for the diseases in animals. In order to better understand how alterations in the sphingolipid metabolism might cause disease, we have completed a study using isolated cells. The results show that altered sphingolipid metabolism is closely associated with the effects of fumonisins on both cell growth and cell death. A portion of the adverse effects can be attributed to the build up of a type of simple sphingolipid which can itself be toxic. Another part of the adverse effect of cells can be attributed to a decrease in more complex sphingolipids which are essential for the normal behavior of cells. The significance of these findings is that they provide insight into strategies for increasing farm animal resistance to the adverse effects of fumonisins.
Technical Abstract: Fumonisin B1 is an inhibitor of ceramide synthase, a key enzyme in de novo sphingolipid biosynthesis and reacylation of free sphingosine. The purpose of this study was to determine the contribution of increased intracellular free sphinganine and decreased complex sphingolipids on cell growth and cell death induced by fumonisin B1 in LLC-PK1 cells. Fumonisin B1 caused an increase in intracellular free sphinganine which preceded depletion of complex sphingolipids, inhibition of cell growth, and cell death. The changes were all fumonisin-concentration- and time-dependent and were well correlated with the increase in free sphingoid bases and depletion of complex sphingolipids. Exogenously added sphinganine mimicked the effects of fumonisin, but beta-chloroalanine, an inhibitor of serine palmitoyltransferase which is the first enzyme in de novo sphingolipid biosynthesis, also inhibited cell growth and increased cell death. When added simultaneously beta-chloroalanine reduced the fumonisin-induced phinganine 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 (~50% to 60%). The results suggest that both the elevation of free sphingoid bases and the decrease in complex sphingolipids contribute to the decreased cell growth and cytolethality of fumonisin B1 in LLC-PK1 cells.