Page 1073 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Fumonisins Chapter | 71 1005

VetBooks.ir groups. Intragastrically dosed groups had 10 20 fold Palmitoyl-CoA + Serine
lower tissue concentrations than did intravenously dosed
groups, and only intravenously dosed groups had measur-
able radioactivity in brain, lung, and adrenal. Thus, it 3-ketosphinganine
3-ketosphinganine
seems that liver and kidney are the primary organs of reductase
fumonisin metabolism and excretion in the pig, and that
Sphinganine
enterohepatic circulation prolongs the persistence of
fumonisin in the body. The toxicokinetics of fumonisin Acyl-CoA
B 1 in horses has not been evaluated.
When pigs were fed fumonisin at daily concentrations Dihydroceramide CoA
between 50 and 500 μg of fumonisin B 1 per kg of body
weight for the last 5 months before slaughter, no muscle
Ceramide Sphingosine
or kidney residues were detected (Liguoro et al., 2004). (sphingosine + fatty acid)
Fumonisin B 1 was not detected in the eggs from laying CoA Acyl-CoA
hens following either intravenous or oral administration Sphingomyelins Glycosphingolipids
(Vudathala et al., 1994). Although negligible concentra-
tions have been shown to cross the mammary barrier (cell membrane turn over)
(Spotti et al., 2001), the toxin was not detected in milk
from cattle that consumed a diet containing fumonisins
(Richard et al., 1996). Therefore, it appears that fumonisin : Pathway blocked by fumonisins
residues in meat, milk, or eggs do not represent a hazard
or food safety concern for humans consuming these
FIGURE 71.2 The effects of fumonisin on the sphingolipid biosyn-
products.
thetic pathway.

MECHANISM OF ACTION binding sites for extracellular matrix proteins as well as
for some microorganisms, microbial toxins, and viruses,
Sphingolipid Alterations
and regulate the behavior of growth factor receptors
Fumonisins are structurally related to sphingosine, the (Merrill and Sweeley, 1996). Complex sphingolipids
major long-chain base backbone of cellular sphingolipids function as precursors for second messengers that mediate
(Fig. 71.1). They are competitive inhibitors of sphinga- cell responses to growth factors, cytokines (including
nine and sphingosine N-acyltransferase (also known as tumor necrosis factor-α), differentiation factors, and
ceramide synthase), key enzymes in the de novo sphingo- 1,25-dihydroxy-vitamin D 3 . Therefore, sphingolipids are
lipid biosynthetic pathway (Fig. 71.2). These N-acyltrans- involved in the regulation of cell growth, cell to cell com-
ferase enzymes are responsible for catalyzing the munication, differentiation, and neoplastic transformation
acylation of sphinganine and the reutilization of sphingo- (Hannun and Bell, 1989).
sine derived from sphingolipid turnover. This inhibition This enzyme inhibition by fumonisin produces a dis-
by fumonisin has been characterized in vitro using liver ruption of sphingolipid metabolism resulting in increased
and brain microsomes, as well as in intact mammalian sphinganine and sphingosine along with a decrease in
cells in culture (hepatocytes, neurons, renal cells, and complex sphingolipids in the serum and tissues of animals
macrophages) (Merrill et al., 1995). Fumonisin B 1 blocks (Wang et al., 1991). These elevations in concentrations of
the incorporation of radiolabeled serine into the sphingoid sphinganine and sphingosine have also been observed
base backbone of ceramides and complex sphingolipids in vivo in several species including pigs, horses, and
and prevents the conversion of sphinganine to sphingosine calves (Goel et al., 1996; Mathur et al., 2001; Riley et al.,
via addition of the 4,5 trans double bond, which occurs 1993; Smith et al., 1999; Smith et al., 2000). This disrup-
after acylation of sphinganine. Fumonisin also blocks rea- tion of sphingolipid metabolism is generally accepted as
cylation of sphingoid bases (primarily sphingosine) the probably mechanism of fumonisin toxicity; however,
released by hydrolysis of more complex sphingolipids only in pigs has the pathophysiology been definitively
(Merrill et al., 1995). determined.
Sphingolipids are located in cellular membranes, lipo- PPE has been shown to be a direct result of acute left-
proteins (especially low-density lipoproteins), and other sided heart failure related to an increase in plasma and
lipid-rich structures. Complex sphingolipids are critical myocardial sphinganine and sphingosine concentrations
for the maintenance of membrane structure, particularly (Constable et al., 2000; Smith et al., 1999,
microdomains such as caveolae. They also serve as 2000). Sphingosine is an important intracellular second