IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

FUMONISIN B 1
ability of fumonisin to alter the function of specific glycosphingolipids and lipid rafts
(membrane associations of sphingolipids, ceramide-anchored proteins and other lipids).
Examples of these functions are inhibition of folate transport, bacterial toxin binding and
transport (e.g., Shigella and cholera toxin), cell–cell and cell–substratum contact and cell–
cell communication (WHO, 2000; Riley et al., 2001; Merrill et al., 2001; WHO, 2002).
(i) Increased dihydroceramide in vivo
In fumonisin-treated animals (pigs, horses, mice), there is an increased amount of
complex sphingolipids containing sphinganine as the long-chain sphingoid-base backbone
(see for example, Riley et al., 1993). The ceramide generated from these complex
sphingolipids is dihydroceramide, which is inactive in ceramide signalling and does not
induce death of oxidant-damaged hepatocytes (Arora et al., 1997). Dihydroceramide is
also enriched in mouse hepatoma-22 cells, in which sphinganine comprised 37% of the
ceramides as compared with 5% in normal rat liver (Rylova et al., 1999).
(j) Hypothesized cellular mechanism
In cultured cells, the balance between the intracellular concentration of sphingolipid
effectors that protect cells from apoptosis (decreased ceramide, increased sphingosine
1-phosphate) and the effectors that induce apoptosis (increased ceramide, increased free
sphingoid bases, increased fatty acids) determines the observed cellular response
(reviewed in Merrill et al., 2001; Riley et al., 2001). Cells sensitive to the proliferative
effect of decreased ceramide and increased sphingosine 1-phosphate will be selected to
survive and proliferate. Conversely, when the increase in free sphingoid bases exceeds
the ability of a cell to convert sphinganine/sphingosine to dihydroceramide/ceramide or
their sphingoid base 1-phosphate, free sphingoid bases will accumulate to toxic levels.
Cells that are sensitive to sphingoid base-induced growth arrest will cease growing and
insensitive cells will survive. Thus, the kinetics of fumonisin B 1 elimination (rapid), the
affinity of fumonisin B 1 for ceramide synthase (competitive and reversible) and the
kinetics of fumonisin-induced sphinganine elevation will influence the time course,
amplitude and frequency of variations in the concentration of intracellular ceramide,
sphingoid base-1 phosphates and free sphinganine in tissues of animals consuming
fumonisins (Enongene et al., 2002a,b). This is important, because the balance between
the rates of apoptosis and cell proliferation is a critical determinant in the process of
hepato- and nephrotoxicity and tumorigenesis in animal models (Dragan et al., 2001;
Howard et al., 2001; Voss et al., 2001). At the cellular level, it is hypothesized that apoptotic
necrosis should be considered to be similar to oncotic necrosis (as defined in Levin
et al., 1999), in that both will lead to a regenerative process involving sustained cell
proliferation (Dragan et al., 2001; Hard et al., 2001). Numerous endogenous processes
can cause DNA damage that, if unrepaired, can give rise to a mutation in the DNA.
Increased cell proliferation may thus involve replication of mutated DNA, resulting in an
increased risk for cancer (Dragan et al., 2001).
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