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-PK1),
fumonisin B1 induces increased tumour
necrosis factor alpha (
TNFalpha) expression independent of the accumulation of sphingoid bases. The objective of this study was to investigate pharmacological approaches for intervening in
fumonisin B1 toxicity using the LLC-PK1 cell model. The toxicity of
fumonisin B1 was assayed using cell viability and
lactate dehydrogenase (
lactate dehydrogenase) release. Pretreatment of cells with
myriocin, preventing
sphinganine accumulates, prevented the
fumonisin B1-induced decrease in cell viability and increased
lactate dehydrogenase release. Modulation of
adenosine receptor activity did not reduce the
fumonisin B1 cytotoxicity. As with
myriocin,
silymarin pretreatment prevented the
fumonisin B1-induced effects on cell viability and
lactate dehydrogenase release. When added 6 or 24 hr
after treatment of cells with
fumonisin B1, 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 B1-treated cells.
Silymarin, unlike
myriocin, induced expression of
TNFalpha to an extent similar to
fumonisin B1, but pretreatment with
silymarin decreased the
fumonisin B1-induced
TNFalpha expression in LLC-PK1 cells. Results suggest that the mechanisms by which
myriocin and
silymarin protect renal cells are different, and
silymarin potentially prevents
fumonisin B1-induced toxicity by modulating
TNFalpha expression or signals downstream of the inhibition of
ceramide synthase.