Abstract: Fumonisin B1 is a mycotoxin commonly found on corn. It is hepatotoxic and nephrotoxic in domestic and experimental animals, and causes equine leukoencephalomalacia and porcine pulmonary oedema. It is a potent inhibitor of ceramide synthase. Inhibition leads to accumulation of free sphingoid bases in cells and tissues. In pig kidney epithelial cells (LLC-PK 1), fumonisin B 1 induces increased tumour necrosis factor α (TNFα) expression independent of the accumulation of sphingoid bases. The objective of this study was to investigate pharmacological approaches for intervening in fumonisin B 1 toxicity using the LLC-PK 1 cell model. The toxicity of fumonisin B 1 was assayed using cell viability and lactate dehydrogenase (lactate dehydrogenase) release. Pretreatment of cells with myriocin, preventing sphinganine accumulates, prevented the fumonisin B 1 induced decrease in cell viability and increased lactate dehydrogenase release. Modulation of adenosine receptor activity did not reduce the fumonisin B 1 cytotoxicity. As with myriocin, silymarin pretreatment prevented the fumonisin B 1-induced effects on cell viability and lactate dehydrogenase release. When added 6 or 24 hr after treatment of cells with fumonisin B 1, both myriocin and silymarin reversed the decreased cell viability and suppressed the increased lactate dehydrogenase release. Myriocin, but not silymarin, blocked the accumulation of sphinganine in fumonisin B 1-treated cells. Silymarin, unlike myriocin, induced expression of TNFα to an extent similar to fumonisin B 1, but pretreatment with silymarin decreased the fumonisin B 1-induced TNFα expression in LLC-PK 1 cells. Results suggest that the mechanisms by which myriocin and silymarin protect renal cells are different, and silymarin potentially prevents fumonisin B 1-induced toxicity by modulating TNFα expression or signals downstream of the inhibition of ceramide synthase.
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Document Type: Original Article
Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia 30602, and
Toxicology and Mycotoxin Research Unit, USDA-ARS, Athens, Georgia 30604, U.S.A.
May 1, 2002
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