Metabolism of T-2 toxin by rat liver carboxylesterase

Johnsen, Hanne; Odden, Erling; Lie, Ø.; Johnsen, Bjørn A.; Fonnum, Frode

doi:10.1016/0006-2952(86)90111-5

Cited by 30 publications

(15 citation statements)

References 19 publications

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“…It was strongly present in mice, but weak in dogs and cats. A microsomal, nonspecific carboxylesterase [EC 3.1.1.1] from liver is known to selectively hydrolyse the C-4 acetyl group of T-2 toxin to yield HT-2 toxin (Johnsen et al, 1986;Yoshizawa et al, 1984). Deoxygenation of the epoxide group yields deepoxy metabolites, which are essentially nontoxic (Swanson et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Localization of Satratoxin-G in Stachybotrys chartarum Spores and Spore-Impacted Mouse Lung Using Immunocytochemistry

et al. 2004

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Satratoxin-G (SG) is the major macrocyclic trichothecene mycotoxin produced by Stachybotrys chartarum (atra) and has been implicated as a cause of a number of animal and human health problems including pulmonary hemorrhage in infants. However, there is little understanding where this toxin is localized in the spores and mycelial fragments of this species or in the lung impacted by SG-sequestered spores. The purpose of this study was to evaluate the distribution of SG in S. chartarum spores and mycelium in culture, and spore-impacted mouse lung in vivo, using immunocytochemistry. SG was localized predominately in S. chartarum spores with moderate labelling of the phialide-apex walls. Labelling was primarily along the outer plasmalemma surface and in the inner wall layer. Only modest labelling was observed in hyphae. Toxin localization at these sites supports the position that spores contain the highest satratoxin concentrations and that the toxin is constitutively produced. In impacted mouse lung, highest SG labelling was detected in lysosomes, along the inside of the nuclear membrane in nuclear heterochromatin and RER within alveolar macrophages. Alveolar type II cells also showed modest labelling of the nuclear heterochromatin and RER. There was no evidence that the toxin accumulated in the neutrophils, fibroblasts, or other cells associated with the granulomas surrounding spores or mycelial fragments. These observations indicate that SG displays a high degree of cellular specificity with respect to its uptake in mouse lung. They further indicate that the alveolar macrophages play an important role in the sequestration and immobilization of low concentrations of the toxin.

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Section: Discussionmentioning

confidence: 99%

Localization of Satratoxin-G in Stachybotrys chartarum Spores and Spore-Impacted Mouse Lung Using Immunocytochemistry

et al. 2004

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“…Johnsen et al . [ 14 ] found that T-2 toxin was rapidly hydrolyzed into the main metabolite HT-2 toxin by carboxylesterase in a rat liver microsomal fraction.…”

Section: Introductionmentioning

confidence: 99%

The roles of carboxylesterase and CYP isozymes on the in vitro metabolism of T-2 toxin

Lin

Chen

et al. 2015

Military Med Res

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BackgroundT-2 toxin poses a great threat to human health because it has the highest toxicity of the currently known trichothecene mycotoxins. To understand the in vivo toxicity and transformation mechanism of T-2 toxin, we investigated the role of one kind of principal phase I drug-metabolizing enzymes (cytochrome P450 [CYP450] enzymes) on the metabolism of T-2 toxin, which are crucial to the metabolism of endogenous substances and xenobiotics. We also investigated carboxylesterase, which also plays an important role in the metabolism of toxic substances.MethodsA chemical inhibition method and a recombinant method were employed to investigate the metabolism of the T-2 toxin by the CYP450 enzymes, and a chemical inhibition method was used to study carboxylesterase metabolism. Samples incubated with human liver microsomes were analyzed by high performance liquid chromatography-triple quadrupole mass spectrometry (HPLC- QqQ MS) after a simple pretreatment.ResultsIn the presence of a carboxylesterase inhibitor, only 20 % T-2 toxin was metabolized. When CYP enzyme inhibitors and a carboxylesterase inhibitor were both present, only 3 % of the T-2 toxin was metabolized. The contributions of the CYP450 enzyme family to T-2 toxin metabolism followed the descending order CYP3A4, CYP2E1, CYP1A2, CYP2B6 or CYP2D6 or CYP2C19.ConclusionCarboxylesterase and CYP450 enzymes are of great importance in T-2 toxin metabolism, in which carboxylesterase is predominant and CYP450 has a subordinate role. CYP3A4 is the principal member of the CYP450 enzyme family responsible for T-2 toxin metabolism. The primary metabolite produced by carboxylesterase is HT-2, and the main metabolite produced by CYP 3A4 is 3′-OH T-2. The different metabolites show different toxicities. Our results will provide useful data concerning the toxic mechanism, the safety evaluation, and the health risk assessment of T-2 toxin.

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“…However, CES1C5 may not be the dominant enzyme catalyzing this reaction as ester hydrolysis products of T-2 or HT-2 were similar between the control and HepG2-CES1C5 groups. Carboxylesterases have the highest levels of activity in liver microsomes, and are separated into at least five different subfamilies (CES1-5) (60,61). The increased carboxylesterases in the present study, specifically porcine CES1C4 and CES1C5, shared 96% identity at the amino acid level and belonged to the same isoenzyme subfamily (CES1C).…”

Section: T-2 Toxin Biotransformationmentioning

confidence: 74%

Integrated Transcriptional and Proteomic Analysis with In Vitro Biochemical Assay Reveal the Important Role of CYP3A46 in T-2 Toxin Hydroxylation in Porcine Primary Hepatocytes

Wang

Jiang

Zhang

et al. 2011

Molecular & Cellular Proteomics

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Both T-2 toxin and its metabolites are highly potent mycotoxins that can cause severe human and animal diseases upon exposure. Understanding the toxic mechanism and biotransformation process of T-2 toxin at a cellular level is essential for the development of countermeasures. We investigated the effect of T-2 toxin in porcine primary hepatocytes using porcine genome array and two-dimensional difference gel electrophoresis with matrix-assisted laser desorption/ionization tandem time of flight mass spectrometry. Integrated transcriptional and proteomic analysis demonstrated that T-2 toxin adversely affected porcine hepatocytes by initiating lipid metabolism disorder, oxidative stress response, and apoptosis. In addition, xenobiotic metabolism genes, including cytochrome P450 3As (CYP3A46 and CYP3A39), carboxylesterase 1Cs (CES1C4 and CES1C5), and epoxide hydrolase (EPHX1), increased in T-2 toxin treatment cells. Using HepG2 cells to over-express the recombinant xenobiotic metabolism genes above and rapid resolution liquid chromatography/tandem mass spectrometry to detect metabolites of T-2 toxin, we determined that porcine CYP3A46 mainly catalyzed T-2 to form 3-hydroxy-T-2, which was further confirmed by purified CYP3A46 protein. However, recombinant porcine CES1C5 and EPHX1 did not enhance hydrolysis and

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Metabolism of T-2 toxin by rat liver carboxylesterase

Cited by 30 publications

References 19 publications

Localization of Satratoxin-G in Stachybotrys chartarum Spores and Spore-Impacted Mouse Lung Using Immunocytochemistry

Localization of Satratoxin-G in Stachybotrys chartarum Spores and Spore-Impacted Mouse Lung Using Immunocytochemistry

The roles of carboxylesterase and CYP isozymes on the in vitro metabolism of T-2 toxin

Integrated Transcriptional and Proteomic Analysis with In Vitro Biochemical Assay Reveal the Important Role of CYP3A46 in T-2 Toxin Hydroxylation in Porcine Primary Hepatocytes

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