STRUCTURE-FUNCTION RELATIONSHIP OF T-2 TOXIN AND ITS METABOLITES IN INDUCING THYMIC APOPTOSIS IN-VIVO IN MICE

Recently we found that a single administration of T-2 toxin (T-2), a t richothecene mycotoxin, into mice induced DNA fragmentation, a biochem ical hallmark of apoptosis, in the thymus.(1)) In this study, we inves tigated the effective chemical structure(s) of T-2-derived metabolites capable of inducing thymic apoptosis in vivo in mice. Metabolic conve rsion of T-2 to 3'-hydroxy-T-2 toxin (3'-OH-T-2) (Fig. 1) did not dimi nish the apoptosis-inducing activity, since essentially the same level of fragmented DNA was detected in the thymus taken from mice injected with either T-2 or 3'-OH-T-2. In contrast, hydrolysis of T-2 and 3'-O H-T-2 at the carbon-4 (C-4) position to HT-2 toxin (HT-2) and 3'-hydro xy-HT-2 toxin (3'-OH-HT-2), respectively, greatly decreased the level of DNA fragmentation. Similarly, hydrolysis of T-2 at the carbon-8 (C- 8) position to neosolaniol strongly diminished its ability to induce D NA fragmentation. T-2 tetraol, having no ester groups, was unable to i nduce apoptosis. Based on the data presented in this study, we conclud ed that both the acetyl group at the C-4 position and the isovaleryl o r 3'-hydroxyisovaleryl group at the C-8 position of the T-2 molecule a re important for inducing cell death through apoptosis in the thymus.