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 trichothecene mycotoxin, into mice induced DNA fragmentation, a biochemical hallmark of apoptosis, in the thymus. In this study, we investigated the effective chemical structure(s) of T-2-derived metabolites capable of inducing thymic apoptosis in vivo in mice. Metabolic conversion of T-2 to 3'-hydroxy-T-2 toxin (3'-OH-T-2) did not diminish 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'-OH-T-2 at the carbon-4 (C-4) position to HT-2 toxin (HT-2) and 3'-hydroxy-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 DNA fragmentation. T-2 tetraol, having no ester groups, was unable to induce apoptosis. Based on the data presented in this study, we concluded that both the acetyl group at the C-4 position and the isovaleryl or 3'-hydroxyisovaleryl group at the C-8 position of the T-2 molecule are important for inducing cell death through apoptosis in the thymus.
Faculty of Agriculture, Kagawa University, Japan.
Z
Z
Islam
M
M
Nagase
A
A
Ota
S
S
Ueda
T
T
Yoshizawa
N
N
Sakato
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002849:Chromatography, Gas; D003124:Colorimetry; D053938:DNA Fragmentation / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005434:Flow Cytometry; D005670:Fusarium / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D011897:Random Allocation; D013329:Structure-Activity Relationship; D013605:T-2 Toxin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000737:chemistry; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects; D013997:Time Factors
D013605:T-2 Toxin