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Abstract
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.
Highlights
Trichothecenes are a group of mycotoxins produced by several filamentous fungi including Fusarium
3-hydroxytrichothecenes in cytotoxicity and animal studies, we first verified the extent of the deacetylation of two trichothecenes, 3-ADON, which is an acetylated form of the most common trichothecene DON, and, ITD, the first acetylated trichothecene produced by Tri101p in trichothecene biosynthesis
ITDol was detected in H2 O containing its corresponding 3-acetyltrichothecene, but some deacetylated forms were detected in both the buffer and the RPMI medium after incubation (Supplementary Table S1), which suggests that non-enzymatic deacetylation of these 3-acetylated trichothecenes occurred in them
Summary
Trichothecenes are a group of mycotoxins produced by several filamentous fungi including Fusarium They have a trichothecene skeleton of 12,13-epoxytrichothec-9-ene in common, but their side chain modification greatly varies, resulting in a large difference in their toxicity [1,2]. In non-fusaria, including Myrothecium, Trichoderma, Trichothecium, Stachybotrys, and Spicellum [7], trichodiene is oxygenated to isotrichodiol followed by spontaneous cyclization to produce d-type trichothecenes. In order to combat Fusarium head blight, researchers have made extensive efforts to examine the effect of the transgenic expression of Tri101 on trichothecene resistance and Fusarium infection in host cereals [18]. We examined whether Tri101 transfection into mammalian cultured cells improves their resistance to 3-hydorxytrichothecenes
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