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Title: MYCOTOXIN-INDUCED ELEVATION OF FREE SPHINGOID BASES IN PRECISION-CUT RAT LIVER SLICES: SPECIFICITY OF THE RESPONSE AND STRUCTURE-ACTIVITY RELATIONSHIPS

Author
item Norred, William
item Plattner, Ronald
item Dombrink Kurtzman, Mary Ann
item Meredith, Filmore
item Riley, Ronald

Submitted to: Journal of Toxicology and Applied Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/24/1997
Publication Date: N/A
Citation: N/A

Interpretive Summary: A group of chemical compounds known as fumonisins are produced by some types of molds that grow on corn. These compounds are toxic to animals fed moldy corn, even causing death. Fumonisins could also be involved in some types of human disease, especially in regions of Africa and China where moldy food is often consumed. Once consumed, fumonisins interfere with the ability of the body's cells to manufacture a particular type of fat. These fats are known as sphingolipids, and they are very important for the proper functioning of all cells. The interference is most likely the mechanism by which fumonisins cause illness. In this paper, we report the relative ability of several different fumonisins, or analogs, to block sphingolipid formation. Most of the analogs tested were about equal in ability, but some had reduced activity, and one had no activity, The toxins with reduced activity were modified fumonisins that are formed during the processing of corn to make masa flour used to make tortillas. Thus, this centuries old processing method may reduce the danger of consuming moldy corn. The fumonisin that had no effect on sphingolipids we predict will also have not toxicity, but this is yet to be tested. We also tested other common mold toxins that are unrelated to fumonisins, and therefore differ chemically. None of the ones we tested blocked sphingolipid formation. This finding is important because the effect of fumonisins on sphingolipids has been proposed as an early diagnostic indicator of fumonisin ingestion. If the response was a nonspecific response of cells to any toxin, then the diagnostic test would be no good.

Technical Abstract: Fumonisin B1 (FB1) is the predominant member of a family of toxic metabolites produced by several species of Fusarium, and is commonly found on corn. FB1 is a potent competitive inhibitor of ceramide synthase, which catalyzes the conversion of sphinganine (Sa) and sphingosine (So) to ceramide. The resultant accumulation of free sphingoid bases and the disruption of sphingolipid metabolism is believed to be the mechanism of toxicity of the fumonisins. We determined the relative potency of analogs of FB1 to inhibit ceramide synthase, as measured by the elevation of free Sa and Sa:So in rat liver slices. Fumonisins B1, B2, B3, B4, C4 and TA toxin (a structurally similar mycotoxin produced by the tomato pathogen, Alternaria alternata f. Sp. lycopersici) were approximately equipotent inhibitors. Hydrolyzed fumonisins B1, B2 and B3, which lack the tricarballylic side chains, were only 30-40% as potent as the parent toxins. N-acetylated FB1 (FA1) did not block ceramide synthase, suggesting that FA1 is non-toxic. The ability of relatively high (10 and 100 macro-molar) doses of other mycotoxins that bear no structural similarity to fumonisins, including aflatoxin B1, cyclopiazonic acid, beauvericin, T-2 toxin, sterigmatocystin, luteoskyrin, verrucarin A, scirpentriol and zearalenone, to block ceramide synthase was also determined. All of the toxins tested were negative in the bioassay with the exception of fumonisins, indicating that disruption of sphingolipid metabolism is a specific cytotoxic response.