Structure-Function Relationship of 12, 13 Epoxytrichothecene Mycotoxins in Cell Culture; Comparison to Whole Animal Lethality

摘要

Nineteen 12,13-epoxytrichothecene mycotoxins were tested for their relative capabilities to inhibit protein synthesis in Vero cells and rat spleen lymphocytes. Although the lymphocytes were generally more sensitive to the mycotoxins, good correlation existed between the relative potencies of the various trichothecenes in the two cell systems. The most potent mycotoxins (T-2, verrucarin A, and roridin A) have acetyl side groups on, or a hydrocarbon chain between carbons 4 and 15 of the basic ring structure. Loss of side groups from either of these positions or an isovaleryl group at carbon 8, resulted in reduced protein synthesis inhibition (T-2 to HT-2 neosolaniol or diacetoxyscirpenol). Any combination of loss from all three positions (T-2 triol T-2 tetraol, 15-monoacetyl DAS scirpentriol, fusarenon X, and deoxynivalenol) further weakens their effect. Reduction of the hydroxyl groups to hydroxides, forming verrucarol and deoxyverrucarol reduced their effectiveness by over three logs compared to the most potent mycotoxins. Addition of side groups resulted in reduced effectiveness only when an acetyl group was added to the carbon 3 position of T-2 (acetyl T-2) and deoxynivalenol (3-acetyl deoxynivalenol), and substitution of an epoxide across the 9,10 carbons of diacetoxyscirpenol (Beta-epoxide DAS). Effects of combining these and other mycotoxins were additive and showed no synergism or competition for binding to the active site.