IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

FUMONISIN B 1
Figure 3. Proposed model illustrating how the tricarboxylic acid groups and free
amino group of fumonisin B 1 mimic the fatty acyl–coenzyme A (CoA) and free
sphinganine substrates, respectively, in the active site of ceramide synthase. For
fumonisin B 1, the interaction is primarily electrostatic; for the normal substrates,
there are also hydrophobic interactions involving partitioning into the lipid bilayer
Modified from Merrill et al. (1996, 2001)
(c) Sphingoid base accumulation
When ceramide synthase is completely inhibited, either in vitro or in vivo, the intracellular
sphinganine and sometimes sphingosine concentration increases rapidly. In vivo
there is a close relationship between the amount of sphinganine accumulated and the
expression of fumonisin toxicity in liver and kidney (Riley et al., 1994a,b; Tsunoda
et al., 1998; Riley et al., 2001; Voss et al., 2001). Accumulated free sphingoid bases can
persist in tissues (especially kidney) much longer than fumonisin B 1 (most recently
shown by Enongene et al., 2000; Garren et al., 2001; Enongene et al., 2002a,b). In urine
from rats fed fumonisin B 1, nearly all the free sphinganine is recovered in dead cells. A
sub-threshold dose in rats or mice can prolong the elevation of free sphinganine in urine
or kidney caused by a higher dose (Wang et al., 1999; Enongene et al., 2002a,b). Fumonisin
B 1-induced elevation of free sphingoid base levels and toxicity are both reversible,
although elimination of free sphinganine from the liver is more rapid than from the
kidney (Enongene et al., 2000; Garren et al., 2001; Enongene et al., 2002a,b).
In ponies given fumonisin B 1-contaminated feed, changes in the sphinganine/sphingosine
ratio in serum were seen before hepatic enzymes were notably elevated (Wang
et al., 1992; Riley et al., 1997).
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