Fusarium graminearum causes a disease of wheat and barley known as Fusarium head blight. It contaminates the grains with trichothecene mycotoxins such as deoxynivalenol (DON). As shunt intermediates in the DON biosynthetic pathway, 7-hydroxyisotrichodermin (7-HIT) and 8-hydroxyisotrichodermin (8-HIT) are known. However, their activities have not been previously evaluated. In this study, we performed toxicity assays of these trichothecenes by using a sensitive yeast bioassay that we have recently established. The IC 50 of 7-HIT and 8-HIT were in the range of 20-40 µg/ml, while the IC 50 of DON was approximately 1.5 µg/ml. Although the toxicity of these shunt metabolites remains to be investigated in animal systems, our present data indicate that 7-HIT and 8-HIT may not be major issues that require regulation in agricultural products.
In trichothecene-producing fusaria, isotrichodermol (ITDol) is the first intermediate with a trichothecene skeleton. In the biosynthetic pathway of trichothecene, a 3-O-acetyltransferase, encoded by Tri101, acetylates ITDol to a less-toxic intermediate, isotrichodermin (ITD). Although trichothecene resistance has been conferred to microbes and plants transformed with Tri101, there are no reports of resistance in cultured mammalian cells. In this study, we found that a 3-O-acetyl group of trichothecenes is liable to hydrolysis by esterases in fetal bovine serum and FM3A cells. We transfected the cells with Tri101 under the control of the MMTV-LTR promoter and obtained a cell line G3 with the highest level of C-3 acetylase activity. While the wild-type FM3A cells hardly grew in the medium containing 0.40 μM ITDol, many G3 cells survived at this concentration. The IC50 values of ITDol and ITD in G3 cells were 1.0 and 9.6 μM, respectively, which were higher than the values of 0.23 and 3.0 μM in the wild-type FM3A cells. A similar, but more modest, tendency was observed in deoxynivalenol and 3-acetyldeoxynivalenol. Our findings indicate that the expression of Tri101 conferred trichothecene resistance in cultured mammalian cells.
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