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Title: Inducible nitric oxide has protective effect on fumonisin B1 hepatotoxicity in mice via modulation of sphingosine kinase

Author
item SUZUKI, HIROFUMI - VET MED/UGA, ATHENS, GA
item Riley, Ronald
item SHARMA, RAGHUBIR - VET MED/UGA, ATHENS, GA

Submitted to: Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/1/2007
Publication Date: 7/1/2007
Citation: Suzuki, H., Riley, R.T., Sharma, R.P. 2007. Inducible nitric oxide has protective effect on fumonisin B1 hepatotoxicity in mice via modulation of sphingosine kinase. Toxicology 229:42-53.

Interpretive Summary: Fumonisin B1, a toxic chemical produced by a mold that is frequently found in corn worldwide. It is toxic to both liver and kidney and causes a brain disease in horses and a lung disease in pigs. Many years ago, USDA scientists working with scientists from Emory University discovered that fumonisins are toxic because they cause changes in the metabolisms of a poorly studied group of fats called sphingolipids. When animals eat corn that contains fumonisins there is an accumulation of some of the sphingolipids and a decrease in others. These changes in the unique fats are known to cause many changes in other important molecules inside cells that act as signals for controlling how cells survive, die and behave under stress. One of the important signaling molecules in cells is a gas known as nitric oxide. It is produced by a special protein known as nitric oxide synthase. We have found that fumonisin can increase the amount of nitric oxide that is produced and that this actually protects cells from fumonisin toxicity. This was accomplished by using mice that were deficient in the protein required for production of nitric oxide. The results show that when mice cannot make nitric oxide that the levels of specific sphingolipids that protect liver from fumonisin toxicity are not produced and the amount of damage to the liver is increased.

Technical Abstract: Fumonisin B1, a mycotoxin, is an inhibitor of ceramide synthase causing marked dysregulation of sphingolipid metabolism in cells. This mycotoxin causes accumulation of free sphingoid bases (sphingosine and dihydrosphingosine or sphinganine) and their metabolites, important messengers involved in signal transduction leading to either cell survival or death. Free sphingoid bases are known apoptotic molecules whereas sphingosine 1-phosphate is protective. We previously reported that fumonisin B1 caused sphingosine kinase (SPHK) induction along with the increase of serine palmitoyltransferase (SPT). Fumonisin B1 also induced inducible nitric oxide synthase (iNOS) expression. In the current study we employed a mouse strain with the targeted deletion of iNOS gene (Nos-KO) to evaluate the role of nitric oxide (NO) on fumonisin B1-induced hepatotoxicity. The Nos-KO mice exhibited increased hepatotoxicity after subacute fumonisin B1 exposure compared to their wild type counterparts, the liver regeneration was lower in Nos-KO compared to that in the WT mice. Increased hepatotoxicity in Nos-KO was not related to the extent of free sphingoid base accumulation after fumonisin B1 treatment; however, it was accompanied by a lack of fumonisin B1-induced SPHK induction. The fumonisin B1-induced SPT was unaffected by lack of iNOS gene. Deletion of iNOS gene did not prevent fumonisin B1-dependent induction of inflammatory cytokines, namely tumor necrosis factor alpha (TNF-alpha), interferon gamma and interleukin-12. The lack of fumonisin B1-induced SPHK induction in Nos-KO was supported by a similar effect on phosphorylated metabolites of sphingoid bases; the equilibrium between sphingoid bases and their phosphates is maintained by SPHK. We therefore conclude that iNOS induction produced by fumonisin B1 modulates SPHK activity; the lack of iNOS prevents generation of sphingosine 1-phosphate and deprives cells from its protective effects.