Trichothecene metabolism studies. 2. Structure of 3α-(1″gb-D-glucopyranosiduronyl)-8α-isovaleryloxy-scirpen-3,4β, 15-triol 15-acetate produced from T-2 toxin

Roush, William; Marletta, Michael A.; Russo-Rodriguez, Sandra; Recchia, Joanne

doi:10.1016/s0040-4039(00)95002-0

Cited by 13 publications

(16 citation statements)

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“…Deacetylation of T-2 toxin at position 4 forming HT-2 toxin is one of the most important phase I metabolic reactions, shown for example in microsomes, human cells in primary culture , or animals. ,, Additionally, phase II reactions, especially glucuronidation of T-2 toxin, HT-2 toxin and further phase I metabolites, are essential for the metabolism and excretion. The incubation of T-2 toxin with rat liver microsomes in the presence of uridine 5′-diphosphoglucuronic acid (UDPGA) leads to the formation of HT-2 toxin 3-glucuronide …”

Section: Introductionmentioning

confidence: 99%

HT-2 Toxin 4-Glucuronide as New T-2 Toxin Metabolite: Enzymatic Synthesis, Analysis, and Species Specific Formation of T-2 and HT-2 Toxin Glucuronides by Rat, Mouse, Pig, and Human Liver Microsomes

Welsch

Humpf

2012

J. Agric. Food Chem.

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Glucuronides of the mycotoxin T-2 toxin and its phase I metabolite HT-2 toxin are important phase II metabolites under in vivo and in vitro conditions. Since standard substances are essential for the direct quantitation of these glucuronides, a method for the enzymatic synthesis of T-2 and HT-2 toxin glucuronides employing liver microsomes was optimized. Structure elucidation by nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry revealed that besides T-2 toxin glucuronide and HT-2 toxin 3-glucuronide also the newly identified isomer HT-2 toxin 4-glucuronide was formed. Glucuronidation of T-2 and HT-2 toxin in liver microsomes of rat, mouse, pig, and human was compared and metabolites were analyzed directly by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). A distinct, species specific pattern of glucuronidation of T-2 and HT-2 toxin was observed with interesting interindividual differences. Until recently, glucuronides have frequently been analyzed indirectly by quantitation of the aglycone after enzymatic cleavage of the glucuronides by β-glucuronidase. Therefore, the hydrolysis efficiencies of T-2 and HT-2 toxin glucuronides using β-glucuronidases from Helix pomatia, bovine liver, and Escherichia coli were compared.

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Section: Introductionmentioning

confidence: 99%

HT-2 Toxin 4-Glucuronide as New T-2 Toxin Metabolite: Enzymatic Synthesis, Analysis, and Species Specific Formation of T-2 and HT-2 Toxin Glucuronides by Rat, Mouse, Pig, and Human Liver Microsomes

Welsch

Humpf

2012

J. Agric. Food Chem.

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“…We have previously found that the glucuronides from DAS and T-2 toxin formed the /3-glucuronyl bond only at the C-3 position (6,7), and while glucuronides can be formed from DAS and T-2 toxin,2 the quantitatively significant glucuronides are those that result from conjugation of the hydrolysis products of DAS and T-2 toxin (6, 7). The glucuronides are essentially devoid of toxicity as judged by the ability to inhibit protein synthesis in vitro.…”

Section: Resultsmentioning

confidence: 99%

“…2 The acetyl group at C-4 or C-15 of DAS was DAS rapidly hydrolyzed to form 15-monoacetoxyscirpendiol (15-MA) or 4-monoacetoxyscirpendiol (4-MA) respectively and the remaining acetyl group (at C-15 or C-4) was further hydrolyzed to form scirpentriol (Triol) (Scheme I). Conjugation with glucuronic acid was found to be a concurrent pathway with the hydrolysis reaction (6,7).2 Glucuronidation was highly regiospecific, with the formation of a /3-glycosyl bond only with the hydroxyl group at the C-3 position. While glucuronyl conjugates were found to form with DAS as well as 15-MA and the Triol2 the conjugates derived from the hydrolysis products predominated.…”

Section: Introductionmentioning

confidence: 97%

“…The trichothecene mycotoxins are a group of fungal metabolites that exhibit a range of significant biological properties including cyto-and phytotoxicity (1). The deacylation reaction catalyzed by microsomal carboxylesterase (CE)1 (EC 3.1.1.1) has been shown to be a key step in the metabolic transformation of trichothecene esters2 (2)(3)(4)(5)(6)(7). In general, deacylation of trichothecenes renders them much less toxic.…”

Section: Introductionmentioning

confidence: 99%

“…In general, deacylation of trichothecenes renders them much less toxic. In particular, in our laboratory the metabolic fate of diacetoxyscirpenol (anguidine, DAS) was investigated with rat (6,7) and CD-I mouse hepatic microsomes. 2 The acetyl group at C-4 or C-15 of DAS was DAS rapidly hydrolyzed to form 15-monoacetoxyscirpendiol (15-MA) or 4-monoacetoxyscirpendiol (4-MA) respectively and the remaining acetyl group (at C-15 or C-4) was further hydrolyzed to form scirpentriol (Triol) (Scheme I).…”

Section: Introductionmentioning

confidence: 99%

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Carboxylesterase isoenzyme specific deacylation of diacetoxyscirpenol (anguidine)

Wu¹,

Marletta²

1988

Chem. Res. Toxicol.

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The deacylation reaction of diacetoxyscirpenol (DAS), a trichothecene mycotoxin, was studied by using five carboxylesterase isoenzymes isolated from mouse liver microsomes. The simultaneous isolation of the five microsomal carboxylesterase isoenzymes was accomplished by chromatofocusing. DAS serves as a unique substrate since both acetyl groups are accessible for hydrolysis, providing an opportunity to investigate the regioselective hydrolysis of DAS with the various isoenzymes. A novel basic carboxylesterase isoenzyme, pI 8.4-8.2, was isolated. This isoenzyme exhibits strict regioselectivity toward DAS hydrolysis; only the acetyl group at C-4, but not that at C-15, is hydrolyzed. Moreover, this is the major isoenzyme responsible for the deacylation of DAS in mouse hepatic microsomes. The rate constant determined for deacylation of DAS at C-4 for this isoenzyme is 130-1000 times greater than that of the other carboxylesterases. This isoenzyme was also the most efficient for the hydrolysis of 4-monoacetoxyscirpenediol with a rate constant 30-100 times greater than that of the other isoenzymes.

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Methylthiazolidine‐4‐carboxylate for treatment of acute T‐2 toxin exposure

Frick

Jorge

1991

J of Applied Toxicology

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The effect of T-2 toxin on hepatic glutathione content and the protective effect of 2-methyl-thiazolidine-4-carboxylate (MTCA), an L-cysteine prodrug, were studied in mice. Acute exposure to T-2 toxin (4 mg kg-1, s.c.) resulted in a progressive decrease in glutathione content, reaching a minimum 6-8 h after toxin administration. Because T-2 toxin caused decreased food consumption, a condition known to deplete hepatic glutathione, glutathione was measured in both fed and fasted control and toxin-treated mice. Glutathione content (mumol g-1 tissue) was 9.01 +/- 0.66 (control) and 4.26 +/- 0.41 (toxin) for fed mice, 4.45 +/- 0.39 (control) and 2.45 +/- 0.26 (toxin) for 16-h fasted mice, and 7.18 +/- 0.26 (control) and 3.76 +/- 0.65 (toxin) for mice fed before, but fasted after exposure to toxin. In all cases, toxin treatment resulted in significant decreases in glutathione content compared to controls. Treatment of T-2-intoxicated mice with MTCA (750 mg kg-1, i.p.) not only maintained glutathione content at control levels or higher but significantly improved survival as well. Therefore, the toxicity and lethality of T-2 toxin may be associated with decreased hepatic glutathione content, since MTCA maintained glutathione content and improved survival.

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Trichothecene metabolism studies. 2. Structure of 3α-(1″gb-D-glucopyranosiduronyl)-8α-isovaleryloxy-scirpen-3,4β, 15-triol 15-acetate produced from T-2 toxin

Cited by 13 publications

References 11 publications

HT-2 Toxin 4-Glucuronide as New T-2 Toxin Metabolite: Enzymatic Synthesis, Analysis, and Species Specific Formation of T-2 and HT-2 Toxin Glucuronides by Rat, Mouse, Pig, and Human Liver Microsomes

HT-2 Toxin 4-Glucuronide as New T-2 Toxin Metabolite: Enzymatic Synthesis, Analysis, and Species Specific Formation of T-2 and HT-2 Toxin Glucuronides by Rat, Mouse, Pig, and Human Liver Microsomes

Carboxylesterase isoenzyme specific deacylation of diacetoxyscirpenol (anguidine)

Methylthiazolidine‐4‐carboxylate for treatment of acute T‐2 toxin exposure

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