IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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IARC MONOGRAPHS VOLUME 82
The first proposed lipid-based mechanism involves inhibition of ceramide synthase
(Wang et al., 1991), a key enzyme in the biosynthesis of sphingolipids. In line with
findings in human cell lines (Biswal et al., 2000; Charles et al., 2001), human primary
cell cultures (Tolleson et al., 1999), non-human primates (Van der Westhuizen et al.,
2001) and all other animals tested (reviewed in WHO, 2000, 2002), human exposure to
fumonisins is also associated with evidence of disruption of sphingolipid metabolism
(Qiu & Liu, 2001). Alterations in the free sphinganine/free sphingosine ratio, a consequence
of ceramide synthase inhibition, are now used as a biomarker for exposure to
fumonisins in domestic animals (Riley et al., 1994a,b) and humans (Van der Westhuizen
et al., 1999; Qiu & Liu, 2001; Ribar et al., 2001). Turner et al. (1999) reviewed potential
problems of using sphingoid base ratios as a functional biomarker for exposure to fumonisin
B 1 in humans.
The second biochemical mechanism proposes changes in polyunsaturated fatty acids
and phospholipid pools (Gelderblom et al., 1996b). This mechanism is supported by data
from studies with rat liver (reviewed in WHO, 2002) and human cell lines (Pinelli et al.,
1999; Seegers et al., 2000).
The cellular consequences of both biochemical modes of action provide support for
a non-genotoxic mechanism of carcinogenicity. It is proposed that alterations in cell
growth, death and differentiation due to disruption of lipid-mediated signalling and
regulatory pathways lead to an imbalance between the rates of apoptosis and proliferation
and that this imbalance is a critical determinant in the process of hepato- and
nephrotoxicity and tumorigenesis in animal models (reviewed in WHO, 2002).
4.5.1 Interference with sphingolipid metabolism
(a) Sphingolipid chemistry and function
Sphingolipids are a highly diverse class of lipids found in all eukaryotic cells. The
biological functions are equally diverse: the compounds serve as structural components
required for maintenance of membrane integrity, as receptors for vitamins and toxins, as
sites for cell–cell recognition and cell–cell and cell–substrate adhesion, as modulators of
receptor function and as lipid second messengers in signalling pathways responsible for
cell growth, differentiation and death (Merrill et al., 1997).
(b) Inhibition of ceramide synthase
In every cell line and animal, plant or fungus in which it has been tested, fumonisin
B 1 inhibits the coenzyme A (CoA)-dependent acylation of sphinganine and sphingosine
via interaction with the enzyme sphinganine/sphingosine N-acyltransferase (ceramide
synthase). This enzyme recognizes both the amino group (sphingoid-binding
domain) and the tricarboxylic acid side-chains (fatty acyl-CoA domain) of fumonisin B 1
(Merrill et al., 2001) (Figure 3).