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

Fumonisin B-1 (FB1) is the predominant member of a family of toxic met abolites 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 and sphingosine to ceram ide. The resultant accumulation of free sphingoid bases and the disrup tion of sphingolipid metabolism is believed to be the mechanism of tox icity of the fumonisins. The objectives of this study were to determin e the relative potency of analogs of FB1 to inhibit ceramide synthase and to determine whether the inhibition is specific to mycotoxins with fumonisin-like structures. Fumonisins B-1, B-2, B-3, B-4, C-4, and TA toxin (a structurally similar mycotoxin produced by the tomato pathog en, Alternaria alternata f. sp. lycopersici) were approximately equipo tent inhibitors. Hydrolyzed fumonisins B-1, B-2, and B-3, Which lack t he tricarballylic side chains, were only 30-40% as potent as the paren t toxins. N-acetylated FB1 (FA(1)) did not block ceramide synthase, su ggesting that FA, is nontoxic. Inhibition of ceramide synthase by fumo nisin analogs did not appear to be related to the lipophilicity of the compounds, as determined by computer estimation of log P values. The ability of relatively high (10 and 100 mu M) doses of other mycotoxins that bear no structural similarity to fumonisins, including aflatoxin B-1, cyclopiazonic acid, beauvericin, T-2 toxin, sterigmatocystin, lu teoskyrin, verrucarin A, scirpentriol, and zearalenone, to block ceram ide synthase was also determined. All of the toxins tested were negati ve in the bioassay with the exception of fumonisins, indicating that d isruption of sphingolipid metabolism is a specific cytotoxic response.