Submitted to: Pharmacology and Toxicology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 12/1/2001
Publication Date: N/A
Citation: Interpretive Summary: Fumonisins are toxic chemicals produced by molds that contaminate US corn. The presence of fumonisin in US corn can reduce the value of the corn. The Food and Drug Administration,Center for Veterinary Medicine, has published guidelines for the levels of fumonisins that should not be exceeded in farm animal feeds. The guidelines are based on what is known about the levels of fumonisin in feeds that can cause harm to farm animals. We have found that there are ways to prevent fumonisin toxicity in cultured cells. One treatment involves the use of a chemical (ISP-1) produced by a mold. This chemical prevents the build-up of a toxic fat in the kidney cells and also prevents the toxicity of the fumonisin in these cells. In the present study we found another chemical that protects cells but by an unknown means. This work is important because it shows that there may be several ways to prevent or reduce the farm animal toxicity due to consumption of feeds that contain high levels of the poisonous fumonisins.
Technical Abstract: Fumonisin B1 (FB1) is a mycotoxin commonly found on corn. It is hepato- toxic and nephrotoxic in domestic and research animals, and causes equine leukoencephalomalacia and porcine pulmonary edema. 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-PK1), FB1 induces increased tumor necrosis factor alpha (TNFa) expression independent of the accumulation of sphingoid bases. The objective of this study was to investigate pharmacological approaches for intervening in FB1 toxicity using the LLC-PK1 cell model. The toxicity of FB1 was assayed using cell viability and lactate dehydrogenase (LDH) release. Pretreatment of cells with myriocin, preventing sphinganine accumulation, prevented the FB1-induced decrease in cell viability and increased LDH release. Modulation of adenosine receptor activity did not reduce the FB1 cytotoxicity. As with myriocin, silymarin pretreatment prevented the FB1-induced effects on cell viability and LDH release. When added 6 or 24 hr after treatment of cells with FB1, both myriocin and silymarin reversed the decreased cell viability and suppressed increased LDH release. Myriocin, but not silymarin, blocked accumulation of sphinganine in FB1-treated cells. Silymarin unlike myriocin, induced expression of TNFa to an extent similar to FB1, but pretreatment with silymarin decreased the FB1-induced TNFa expression in LLC-PK1 cells. Results suggest that the mechanisms by which myriocin and silymarin protect renal cells are different, and silymarin potentially prevents FB1-induced toxicity by modulating TNFa expression or signals downstream of inhibition of ceramide synthase.