The gas chromatography-mass spectrometry profile in plasma showed that a large proportion of FX was recovered as NIV /nivalenol/ after administration of FX in both broilers and ducks. In vitro incubation of liver microsomal and cytosolic fractions with FX demonstrated that the liver and kidney are capable of the FX-to-NIV conversion...
Experiments with subfractions of rat liver revealed that fusarenon-X & T-2 toxin were deacetylated at C-4 (R2) by microsomal esterase & yielded nivalenol & HT-2 toxin, respectively. These findings indicate that the trichothecenes admin to mice & rats are metabolized by liver enzyme(s) into deacetylated products, which are then eliminated in the feces & urine.
The HPLC profile of radioactivity of acetonitrile extracts of urine and feces indicated that FX is rapidly metabolized to NIV after being absorbed from the gastrointestinal tract. In vitro incubation of tissue homogenates with (3)H-FX demonstrated that the liver and kidney are the organs responsible for the FX-to-NIV conversion...
...plant metabolites of mycotoxins, also called masked mycotoxins. Mycotoxins are secondary fungal metabolites, toxic to human and animals. Toxigenic fungi often grow on edible plants, thus contaminating food and feed. Plants, as living organisms, can alter the chemical structure of mycotoxins as part of their defence against xenobiotics. The extractable conjugated or non-extractable bound mycotoxins formed remain present in the plant tissue but are currently neither routinely screened for in food nor regulated by legislation, thus they may be considered masked. Fusarium mycotoxins (deoxynivalenol, zearalenone, fumonisins, nivalenol, fusarenon-X, T-2 toxin, HT-2 toxin, fusaric acid) are prone to metabolism or binding by plants, but transformation of other mycotoxins by plants (ochratoxin A, patulin, destruxins) has also been described. Toxicological data are scarce, but several studies highlight the potential threat to consumer safety from these substances. In particular, the possible hydrolysis of masked mycotoxins back to their toxic parents during mammalian digestion raises concerns.
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.
Unlike many other mycotoxins, trichothecenes do not require metabolic activation to exert their biological activity, instead directly reacting with cellular components. Trichothecenes are cytotoxic to most eukaryotic cells due to their powerful ability to inhibit protein synthesis. They do this by freely moving across the plasma membrane and binding specifically to ribosomes with high-affinity. Specifically, they interfere with the active site of peptidyl transferase at the 3'-end of large 28S ribosomal RNA and inhibit the initiation, elongation or termination step of protein synthesis, as well as cause polyribosomal disaggregation. Protein synthesis is an essential function in all tissues, but tissues where cells are actively and rapidly growing and dividing are very susceptible to the toxins. Additionally, binding to ribosomes is thought to activate proteins in downstream signalling events related to immune response and apoptosis, such as mitogen-activated protein kinases. This is known as ribotoxic stress response. Trichothecenes may also induce some alterations in membrane structure, leading to increased lipid peroxidation and inhibition of electron transport activity in the mitochondria. They can further induce apoptosis through generation of reactive oxygen species. Further secondary effects of trichothecenes include inhibition of RNA and DNA synthesis, and also inhibition of mitosis. (L1948, L1949, A2962, A2963, A2964, A2980)
Evaluation: There is inadequate evidence in humans for the carcinogenicity of toxins derived from Fusarium graminearum. No data were available on the carcinogenicity to humans of toxins derived from F. crookwellense and F. culmorum. ... There is inadequate evidence in experimental animals for the carcinogenicity of fusarenone X. ... Overall evaluation: Toxins derived from Fusarium graminearum, F. culmorum and F. crookwellense are not classifiable as to their carcinogenicity to humans (Group 3).
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
3, 无法归类其对人类致癌性的类别。(L135)
3, not classifiable as to its carcinogenicity to humans. (L135)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
健康影响
Trichothecenes have multiorgan effects including anoerxia and weight loss, growth retardation, nervous disorders, cardiovascular alterations, immunodepression, hemostatic derangements, skin toxicity, decreased reproductive capacity, bone marrow damage, and alimentary toxic aleukia. (L1948, L1949, A2964)
脱氧雪腐镰刀菌烯具有多器官效应，包括厌食和体重减轻、生长迟缓、神经系统疾病、心血管改变、免疫抑制、血液凝固失调、皮肤毒性、生殖能力下降、骨髓损伤以及食源性的毒性白细胞减少症。
Trichothecenes have multiorgan effects including anoerxia and weight loss, growth retardation, nervous disorders, cardiovascular alterations, immunodepression, hemostatic derangements, skin toxicity, decreased reproductive capacity, bone marrow damage, and alimentary toxic aleukia. (L1948, L1949, A2964)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
暴露途径
口服、皮肤、吸入和parenteral（被污染的药物）。
Oral, dermal, inhalation, and parenteral (contaminated drugs). (A3101)
Following... ip injection in mice, most of a dose of (3)H-fusarenon-X was rapidly excreted in the urine; almost no radioactivity remained in the tissues after 3 hr.
(3)H-fusarenon-X sc injected in mice was rapidly absorbed from the injection site & distributed to the liver, kidneys, intestines, & other organs. About 25% of the total radioactivity was eliminated in the urine within 24 hr.
Thirty minutes after subcutaneous administration of uniformly labeled (3)H-fusarenone X at 4 mg/kg body weight to mice, activity was found in liver, kidneys, intestines, stomach, spleen, bile and plasma; none was detected in heart, brain or testis. The highest activity, corresponding to 3% of the dose, was observed in the liver. Twelve hours after administration, no label was present in the organs, and 25% of the dose was recovered as metabolized forms of fusarenone X in the urine.
In order to investigate the comparative fates and dispositions of fusarenon-X (FX) in broilers and ducks, FX was administered i.v. or orally (p.o.) to broilers and ducks. The FX and its metabolite (nivalenol, NIV) were determined in plasma and excreta using gas chromatography-mass spectrometry. The plasma concentrations of FX were determined up to 180 and 120 min in broilers and ducks, respectively, after i.v. and p.o. administration. The NIV was eliminated more slowly than its parent compound... Thus, this study demonstrated that FX is absorbed more efficiently in ducks than in broilers, whereas it is eliminated more slowly in ducks than in broiler chickens.
In order to investigate the comparative fates of nivalenol (NIV) and 4-acetyl derivative of NIV (fusarenon-X, FX) in mice, (3)H-FX or (3)H-NIV was given p.o. to mice. Radioactivity was excreted mainly via the urine in mice given (3)H-FX, but mainly via the feces in mice given (3)H-NIV. The plasma radioactivity reached a peak at 30 or 60 min after the administration of (3)H-FX or (3)H-NIV, respectively. The plasma peak level was 5 times higher, and the area under curve (AUC) was 10 times higher, in (3)H-FX-administered than (3)H-NIV-administered mice. These findings clearly demonstrate that FX is absorbed from the gastrointestinal tract more rapidly and efficiently than NIV... Thus this study demonstrated that the higher oral toxicity of FX than NIV that has been observed in mice and rats is due to the efficient absorption of FX than NIV from the gastrointestinal tract, followed by its rapid conversion to NIV by the liver and kidney.
In the biosynthesis of Fusarium trichothecenes, the C-3 hydroxyl group of isotrichodermol must be acetylated by TRI101 for subsequent pathway genes to function. Despite the importance of this 3-O-acetylation step in biosynthesis, Tri101 is both physically and evolutionarily unrelated to other Tri genes in the trichothecene gene cluster. To gain insight into the evolutionary history of the cluster, we purified recombinant TRI3 (rTRI3), one of the two cluster gene-encoded trichothecene O-acetyltransferases, and examined to determine whether this 15-O-acetyltransferase can add an acetyl to the C-3 hydroxyl group of isotrichodermol. When a high concentration of rTRI3 was used in the assay (final concentration, 50 μm), we observed 3-O-acetylation activity against isotrichodermol that was more than 105 times less efficient than the known 15-O-acetylation activity against 15-deacetylcalonectrin. The rTRI3 protein also exhibited 4-O-acetylation activity when nivalenol was used as a substrate; in addition to 15-acetylnivalenol, di-acetylated derivatives, 4,15-diacetylnivalenol, and, to a lesser extent, 3,15-diacetylnivalenol, were also detected at high enzyme concentrations. The significance of the trace trichothecene 3-O-acetyltransferase activity detected in rTRI3 is discussed in relation to the evolution of the trichothecene gene cluster.
abilities to glucosylate the most relevant type A and B trichothecenes. HvUGT13248, which prefers nivalenol over deoxynivalenol, is also able to conjugate C-4 acetylated trichothecenes (e.g., T-2toxin) to some degree while OsUGT79 and Bradi5g03300 are completely inactive with C-4 acetylated derivatives. The type A trichothecenes HT-2 toxin and T-2 triol are the kinetically preferred substrates in the
