Submitted to: Food and Chemical Toxicology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 1/30/2005
Publication Date: 3/1/2005
Citation: He, Q., Riley, R.T., Sharma, R.P. 2005. Myriocin prevents fumonisin B1-induced sphingoid base accumulation in mice liver without ameliorating hepatotoxicity. Food and Chemical Toxicology. 43:969-979. 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 has published guidelines for fumonisins in corn and corn products. The guidelines are based on what is known about the levels of fumonisin in food that can cause harm to animals including liver cancer. The way fumonisins harm liver involves changes in the way that a group of fats called sphingolipids are processed in the liver. It has been shown that if you reverse the effects on the sphingolipids that you can protect the cells from fumonisin toxicity. Myriocin is a chemical that has been shown to protect cells in culture from fumonisin toxicity by preventing some of the accumulation of a sphingolipid called sphinganine. This study used myriocin in mice to see if it would protect mice from fumonisin liver toxicity. It did not protect the mouse liver from toxicity but actually made it worse. One thing that did occur was that myriocin prevented the well documented effects of fumonisin on production of chemicals known as cytokines indicating that the production of cytokines in the mouse liver are dependent on the fumonisin 'induced alterations in sphinganine. In addition, the results indicate that the most likely cause of the fumonisin toxicity in liver is changes in another group of sphingolipids called complex sphingolipids. This is important because it may lead to a better understanding of the mechanism of fumonisin-induced heptocarcinogenesis in mice.
Technical Abstract: Fumonisin B1 (FB1), a mycotoxin produced by Fusarium verticillioides present on corn and corn-based products, causes species- and organ- specific diseases. The hepatotoxic effects of FB1 in mice have been closely correlated with the accumulation of free sphinganine, a marker for ceramide synthase inhibition, and reduced biosynthesis of more complex sphingolipids. It has been shown that FB1 modulates expression of many cell signaling factors. In the current study we used myriocin, a specific inhibitor of serine palmitoyltransferase, to investigate the role of free sphinganine accumulation on FB1-induced hepatotoxicity and increased expression of selected signaling genes in BALB/c mice. The mice were pretreated intraperitoneally daily with 1.0 mg/kg myriocin 30 min before subcutaneous injections of 2.25 mg/kg of FB1 for 3 days. Results showed that myriocin alone was not hepatotoxic and the combination of myriocin plus FB1 completely prevented the FB1-induced elevation of hepatic free sphinganine and prevented the FB1-induced induction of selected cell signaling genes, suggesting that accumulation of free sphinganine and/or its metabolites contribute to the FB1-modulation of the cell signaling factors. However, the combination of myriocin and FB1 did not prevent FB1-increased concentration of plasma alanine aminotransferase and only slightly attenuated aspartate aminotransferase; it did not affect the FB1-induced hepatocyte apoptosis or increased cell proliferation. A longer combined treatment of myriocin and FB1 was highly toxic. The hepatotoxic effects in mice seen in this study are most likely due to a combination of factors including accumulation of free sphinganine, depletion of more complex sphingolipids and sphingomyelin, or other unknown mechanisms.