Absorption, Distribution and Excretion
During the 90-min period after topical application of a single dose of /(3)H-diacetoxyscirpenol/ ([(3)H]DAS), the rat absorbed and retained more [(3)H]DAS and excreted less radioactivity through urine and feces than the mouse. By 24 hr after treatment, the rat had absorbed, excreted, and retained about twice as much [(3)H]DAS as had the mouse (p < 0.05 or < 0.005). At 7 days posttreatment, the rat had absorbed more than four times the amount of [(3)H]DAS than had the mouse (13.1 vs 57.5%; p < 0.005). However, tissues of the mouse retained a higher proportion of administered radioactivity (4.1%) than those of the rat (1.0%; p < 0.05). Total excretion of radiolabel by the rat was approximately sixfold higher than that of the mouse (56 vs 9%; p < 0.005). The ratio of excretion in urine to that in feces in the rat was about 2 to 1 (37 vs 18%) and in the mouse was about 3.5 to 1 (7 vs 2%). Significant differences in the time course of tissue distribution of [(3)H]DAS in the rat and mouse were found when data were expressed as the percentage of absorbed dose present in tissues or as specific radioactivity (dpm) per gram tissue. These results demonstrated a different pattern of absorption, excretion, and tissue distribution of topically administered [(3)H]DAS in rats and mice.

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Metabolism / Metabolites
Trichothecenes are a group of mycotoxins mainly produced by the fungi of Fusarium genus. Consumers are particularly concerned over the toxicity and food safety of trichothecenes and their metabolites from food-producing animals. The metabolism of T-2 toxin, deoxynivalenol (DON), nivalenol (NIV), fusarenon-X (FX), diacetoxyscirpenol (DAS), 3-acetyldeoxy-nivalenol (3-aDON), and 15-acetyldeoxynivalenol (15-aDON) in rodents, swine, ruminants, poultry, and humans are reviewed in this article. Metabolic pathways of these mycotoxins are very different. The major metabolic pathways of T-2 toxin in animals are hydrolysis, hydroxylation, de-epoxidation, and conjugation. After being transformed to HT-2 toxin, it undergoes further hydroxylation at C-3' to yield 3'-hydroxy-HT-2 toxin, which is considered as an activation pathway, whereas transformation from T-2 to T-2 tetraol is an inactivation pathway in animals. The typical metabolites of T-2 toxin in animals are HT-2 toxin, T-2 triol, T-2 tetraol, neosolaniol (NEO), 3'-hydroxy-HT-2, and 3'-hydroxy-T-2, whereas HT-2 toxin is the main metabolite in humans. De-epoxidation is an important pathway for detoxification in animals. De-epoxy products, DOM-1, and de-epoxy-NIV are the main metabolites of DON and NIV in most animals, respectively. However, the two metabolites are not found in humans. Deacetyl can occur rapidly on the acetyl derivatives, 3-aDON, 15-aDON, and FX. DAS is metabolized in animals to 15-monoacetoxyscirpenol (15-MAS) via C-4 deacetylation and then transformed to scirpentriol (SCP) via C-15 deacetylation. Finally, the epoxy is lost, yielding de-epoxy-SCP. De-epoxy-15-MAS is also the main metabolite of DAS. 15-MAS is the main metabolite in human skin. The review on the metabolism of trichothecenes will help one to well understand the fate of these toxins' future in animals and humans, as well as provide basic information for the risk assessment of them for food safety.
Trichothecenes like T-2 toxin, diacetoxyscirpenol, and deoxynivalenol, which occur in feed, are metabolized preponderant in a biphasic way. Oxidation and hydrolysis are carried out in phase 1, while the transformation products are conjugated with glucuronic acid in phase 2; in addition, the epoxide ring is cleaved by the gut microflora. Metabolites of T-2 toxin are HT-2 toxin, 3'-hydroxy-T-2 toxin, 3'-hydroxy-HT-2 toxin, neosolaniol, 4-deacetylneosolaniol, T-2 triol, T-2 tetraol, and de-epoxide T-2 tetraol. Diacetoxyscirpenol is transformed to 15-monoacetoxyscirpenol, scirpenetriol, de-epoxide 15-moneacetoxyscirpenol, and de-epoxide scirpenetriol. Deoxynivalenol undergoes no extensive metabolism; only the production of deoxynivalenol glucuronide and de-epoxide deoxynivalenol is assumed. As trichothecenes are rapid metabolized, the diagnosis of an intoxication by the analysis of samples of pig origin should be hardly possible; for the same reason, the possibility of an enrichment of trichothecene metabolites in edible tissues is graded as low.

Toxicity Data
LC50 (mice) = 11.3 mg/kg

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Interactions
The possible protective effect of a feed additive (Mycofix) against the toxic effects of 4,15-diacetoxiscirpenol (DAS) in growing broiler chickens was investigated in a 21-d fully randomized trial consisting of seven dietary treatments (control with no DAS or Mycofix added, 1 ppm DAS alone, 1 ppm DAS supplemented with 0.75 g/kg Mycofix, 1 ppm DAS supplemented with 1.5 g/kg Mycofix, 2 ppm DAS alone, 2 ppm DAS supplemented with 0.75 g/kg Mycofix, and 2 ppm DAS supplemented with 1.5 g/kg Mycofix). When no feed additive was included, both levels of dietary DAS significantly decreased BW and feed intake and caused oral lesions, with the effect of 2 ppm DAS being more severe. When 1 ppm DAS was added to the diet, supplementation of Mycofix protected against the adverse effects of DAS on feed intake and BW at both levels of inclusion (0.75 and 1.5 g/kg); however, no protection against oral lesions was obtained by Mycofix supplementation. This finding suggests that the adverse effect of DAS on performance is not due to the oral lesions per se but it is likely the result of the systemic absorption of the mycotoxin. When 2 ppm dietary DAS was present in the diet, only partial protection on BW and feed intake was obtained by Mycofix supplementation.
Combinations of /nivalenol/ (NIV) with T2 /toxin/, /diacetoxyscirpenol/ (DAS) or /deoxynivalenol/ (DON) resulted in additive toxicity in the lymphocyte proliferation test, while combinations of DON with T2 or DAS resulted in an inhibition that was slightly lower than what could have been expected from the inhibition produced by the individual toxins. In conclusion, the tested trichothecenes inhibited both proliferation and Ig production in human lymphocytes in a dose-dependent manner with limited variation in sensitivity between individuals. Enhanced Ig production was observed in cell cultures exposed to the lower doses of the toxins. Combined exposure to two of the toxins resulted mainly in additive or antagonistic effects, although synergistic effects cannot be excluded and should be further investigated.
The individual and combined effects of feeding diets containing 300 mg fumonisin B1 (FB1), and 4 mg diacetoxyscirpenol (DAS) or 3 mg ochratoxin A (OA) were evaluated in two experiments using female turkey poults (Nicholas Large Whites) from day of hatch to 3 wk of age. When compared with controls, body weight gains were reduced 30% (Study 1) and 24% (Study 2) by FB1, 30% by DAS, 8% by OA, 46% by the FB1 and DAS combination, and 37% by the FB1 and OA combination. The efficiency of feed utilization was adversely affected by all treatments except FB1 in Experiment 2. Relative weights of the liver were significantly increased by all treatments except the DAS treatment. Serum concentrations of cholesterol were decreased and activities of aspartate aminotransferase and lactate dehydrogenase were increased and several hematological values were altered in poults fed FB1 alone and in combination with either DAS or OA. Results indicate additive or less than additive toxicity, but not toxic synergy, when poults are fed diets containing 300 mg FB1, and 4 mg DAS or 3 mg OA/kg of diet.

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Non-Human Toxicity Values
LD50 Rat ip 750 ug/kg
LD50 Rat oral 7 mg/kg
LD50 Rat iv 1300 ug/kg
LD50 Mouse oral 7300 ug/kg
For more Non-Human Toxicity Values (Complete) data for DIACETOXYSCIRPENOL (6 total), please visit the HSDB record page.

[1]. In vitro effects of diacetoxyscirpenol (DAS) on human and rat granulo-monocytic progenitors. Mycopathologia. 1997;140(1):59-64.

[2]. Mycotoxicosis caused by a single dose of T-2 toxin or diacetoxyscirpenol in broiler chickens. Vet Pathol. 1981 Sep;18(5):652-64.

Anguidine has been reported in Albifimbria verrucaria, Cordyceps polyarthra, and other organisms with data available.
Anguidine is a trichothecene mycotoxin and potent teratogen. Anguidine inhibits initiation of protein synthesis, resulting in the death of rapidly proliferating cells. Anguidine also has been shown to both potentiate and protect against the cytotoxic effects of other drugs. (NCI04)

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Mechanism of Action
Trichothecenes are toxic for actively dividing cells, such as the intestinal crypt epithelium and the hematopoietic cells. The cytotoxicity has been associated with either impairment of protein synthesis by the binding of the compounds to the ribosomes of eukaryotic cells, or the dysfunction of cellular membranes. Inhibition of protein synthesis has been associated with the induction of labile and regulatory proteins, such as IL-2 in immunocytes. Transport of small molecules is impaired in cell membranes by extremely low concentrations of trichothecenes. /Trichothecenes/
Several studies have shown that the mycotoxins T-2 toxin, diacetoxyscirpenol (DAS), deoxynivalenol (DON) and nivalenol (NIV) affect lymphocyte functioning. However, the molecular mechanisms underlying the immunomodulatory effects of these trichothecenes are not defined yet. In this study, the potency of the type A trichothecenes T-2 toxin and DAS, and the type B trichothecenes DON (and its metabolite de-epoxy-deoxynivalenol; DOM-1) and NIV to reduce mitochondrial activity and to induce apoptosis of Jurkat T cells (human T lymphocytes) were examined. T-2 toxin and DAS are much more cytotoxic at low concentrations than DON and NIV as shown by the AlamarBlue cytotoxicity assay. In addition, the mechanism whereby DON and NIV induced cytotoxicity is mainly via apoptosis as we observed phosphatidylserine externalization, mitochondrial release of cytochrome c, procaspase-3 degradation and Bcl-2 degradation. In contrast, type A trichothecenes reduce the mitochondrial activity at approximately 1000-fold lower concentrations than the type B trichothecenes, resulting in necrosis. These data suggest that the mechanisms resulting in cytotoxic effects are different for type A and type B trichothecenes.
To understand the mechanism underlying T-cell toxicity of diacetoxyscirpenol (DAS) from Fusarium sambucinum, its apoptogenic as well as growth retardation activity was investigated in human Jurkat T cells. Exposure to DAS (0.01-0.15 uM) caused apoptotic DNA fragmentation along with caspase-8 activation, Bid cleavage, mitochondrial cytochrome c release, activation of caspase-9 and caspase-3, and PARP degradation, without any alteration in the levels of Fas or FasL. Under these conditions, necrosis was not accompanied. The cytotoxicity of DAS was not blocked by the anti-Fas neutralizing antibody ZB-4. Although the DAS-induced apoptotic events were completely prevented by overexpression of Bcl-xL, the cells overexpressing Bcl-xL were unable to divide in the presence of DAS, resulting from the failure of cell cycle progression possibly due to down-regulation in the protein levels of cdk4 and cyclin B1. The DAS-mediated apoptosis and activation of caspase-8, -9, and -3 were abrogated by either pan-caspase inhibitor (z-VAD-fmk) or caspase-8 inhibitor (z-IETD-fmk). While the DAS-mediated apoptosis and activation of caspase-9 and caspase-3 were slightly suppressed by the mitochondrial permeability transition pore inhibitor (CsA), both caspase-8 activation and Bid cleavage were not affected by CsA. The activated normal peripheral T cells possessed a similar susceptibility to the cytotoxicity of DAS. These results demonstrate that the T-cell toxicity of DAS is attributable to not only apoptosis initiated by caspase-8 activation and subsequent mitochondrion-dependent or -independent activation of caspase cascades, which can be regulated by Bcl-xL, but also interruption of cell cycle progression caused by down-regulation of cdk4 and cyclin B1 proteins.

C19H26O7

366.41

366.167

2270-40-8

15571694

White to off-white solid powder

1.3±0.1 g/cm3

471.2±45.0 °C at 760 mmHg

162-164℃

162.8±22.2 °C

0.0±2.7 mmHg at 25°C

1.561

1.33

1

7

5

26

687

7

CC1=C[C@@H]2[C@](CC1)([C@]3([C@@H]([C@H]([C@H]([C@@]34CO4)O2)O)OC(=O)C)C)COC(=O)C

AUGQEEXBDZWUJY-NMAPUUFXSA-N

InChI=1S/C19H26O7/c1-10-5-6-18(8-23-11(2)20)13(7-10)26-16-14(22)15(25-12(3)21)17(18,4)19(16)9-24-19/h7,13-16,22H,5-6,8-9H2,1-4H3/t13-,14-,15-,16-,17-,18-,19+/m1/s1

[(1S,2R,7R,9R,10R,11S,12S)-11-acetyloxy-10-hydroxy-1,5-dimethylspiro[8-oxatricyclo[7.2.1.02,7]dodec-5-ene-12,2'-oxirane]-2-yl]methyl acetate

Anguidine; Anguidin; Diacetoxyscirpenol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~136.46 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.82 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.82 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)