Modification of fumonisin B1 hepatotoxicity in mice
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Fumonisin B1 (FB1) is a toxic and carcinogenic mycotoxin produced by Fusarium verticillioides present on corn worldwide. Fumonisin B1 disrupts sphingolipid metabolism by inhibiting ceramide synthase and induces expression of cytokines including tumor necrosis factor a (TNFa) in liver leading to perturbation of cell signaling. We hypothesized that FB1 hepatotoxicity in mice can be modulated by interfering with cell signaling factors. Myriocin prevented hepatic free sphinganine accumulation and overexpression of TNFa superfamily cytokines. Myriocin did not alter FB1-induced liver damage; indeed longer treatments with myriocin and FB1 were lethal. This study suggests that additive inhibition of sphingolipid biosynthesis by myriocin and FB1 induces greater toxicity. Free sphinganine and /or its metabolites contributed to the induction of hepatic cytokines by FB1. Kupffer cells are an important source of hepatic cytokine production. Gadolinium chloride depleted Kupffer cells and attenuated increases in circulating enzyme activities, hepatocyte apoptosis, and free sphinganine following FB1 treatment. Both gadolinium and FB1 individually increased expression of selected cell signaling factors in liver; gadolinium did not alter FB1-induced expression of the above genes. Results indicate that Kupffer cells play a role in FB1 liver injury. Decrease of sphinganine accumulation and induction of protective TNFa signaling may partly account for gadolinium’s ameliorating effect on FB1-induced hepatotoxicity. Inhibition of TNFa signaling by either anti-TNFa antibodies or pentoxifylline exacerbated FB1-induced liver damage. Anti-TNFa antibodies did not alter FB1-induced accumulation of free sphingoid bases and expression of TNFa, interleukin (IL)-12, and interferon (IFN) ?; pentoxifylline significantly reduced free sphinganine accumulation and TNFa expression without altering IL-12 and IFN? expression induced by FB1. These findings suggest a partially protective role of TNFa signaling activation in FB1 hepatotoxicity. Silymarin significantly diminished FB1-induced hepatocyte apoptotic death, while it augmented hepatocyte proliferation. Silymarin dramatically potentiated FB1-induced accumulation of free sphinganine and sphingosine in both liver and kidney. Silymarin itself slightly increased expression of hepatic TNFa; however, it prevented FB1-induced expression of genes in the TNFa superfamily. This study suggests that silymarin protected against FB1 liver damage through inhibition of free sphingoid bases signaling.