Nivalenol | 23282-20-4

• 物质功能分类: 分析化学 - 标准品 - 食品和化妆品标准品
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: Nivalenol
• 英文别名: (1S,2R,3S,7R,9R,10R,11S,12R)-3,10,11-trihydroxy-2-(hydroxymethyl)-1,5-dimethylspiro[8-oxatricyclo[7.2.1.02,7]dodec-5-ene-12,2'-oxirane]-4-one
• CAS: 23282-20-4
• 化学式: C₁₅H₂₀O₇
• 分子量: 312.31
• InChiKey: UKOTXHQERFPCBU-YQPARWETSA-N

物化性质

• 熔点：
  222-223℃
• 比旋光度：
  24D +21.54° (c = 1.3 in ethanol)
• 沸点：
  372.24°C (rough estimate)
• 密度：
  1.2307 (rough estimate)
• 闪点：
  2 °C
• 溶解度：
  DMF：30mg/mL； DMSO：25mg/mL；乙醇：30mg/mL； PBS（pH 7.2）：10 mg/mL
• LogP：
  -1.558 (est)
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from methanol
• 蒸汽压力：
  6.89X10-13 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions.
• 旋光度：
  Specific optical rotation: +21.54 deg at 20 °C/D
• 分解：
  Hazardous decomposition products formed under fire conditions. - Carbon oxides, nitrogen oxides (NOx)
• 碰撞截面：
  171.32 Ų [M+Cl]-; 172.28 Ų [M+HCOO]-; 175.07 Ų [M+Na]+

计算性质

• 辛醇/水分配系数(LogP)：
  -1.7
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  120
• 氢给体数：
  4
• 氢受体数：
  7

ADMET

代谢

有证据表明，非反刍动物对雪腐镰刀菌烯醇的去环氧作用程度存在主要物种依赖性差异，这种差异可能发生在某些物种的胃肠道下段。在大鼠、猪和产蛋鸡的粪便中已经检测到了去环氧代谢物，但在小鼠或肉鸡中未检测到，根据体外研究，该物质在人类中形成的可能性也不大。

There is evidence of major species-dependent differences in the extent of de-epoxidation of nivalenol in non-ruminants, which may occur in the lower parts of the gastrointestinal tract in some species. The de-epoxy metabolite has been detected in feces of rats, pigs and laying hens, but not in mice or broiler chickens and, based on in vitro studies, it is unlikely to be formed in humans.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在反刍动物中，与其他三线霉素类似，雪腐镰刀菌烯醇（nivalenol）在吸收前可能在瘤胃中进行广泛的去环氧作用。

In ruminants, it is likely that, as for other trichothecenes, extensive de-epoxidation of nivalenol may occur in the rumen prior to absorption.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Nivalenol is metabolized to de-epoxy nivalenol. 尼瓦连醇被代谢为脱环氧尼瓦连醇。

Nivalenol is metabolized to de-epoxy nivalenol.

来源:Hazardous Substances Data Bank (HSDB)

代谢

雪腐镰刀菌烯类化合物中，脱环氧代谢物对细胞毒性的研究，以及与具有完整环氧基团的相应毒素和它们的乙酰化衍生物的比较。通过5-溴-2'-脱氧尿嘧啶（BrdU）掺入法测定DNA合成，来确定细胞毒性效果。以抑制50%的DNA合成（IC(50)）的浓度来表示NIV和DON的毒性，在相似的微摩尔浓度下发生（1.19±0.06和1.50±0.34 uM）。在实验中，Fusarenon X（4-乙酰NIV）的毒性类似于NIV，而15-AcDON的毒性等于DON。3-AcDON的毒性低于DON和15-AcDON。脱环氧DON的IC(50)值在实验中比DON的IC(50)值高54倍，而脱环氧NIV的IC(50)值比NIV的IC(50)值高55倍。结果验证了之前的发现，即脱环氧是一种解毒反应。

The cytotoxicity of the de-epoxy metabolites of trichothecenes nivalenol (NIV) and deoxynivalenol (DON) was determined and compared with the cytotoxicity of the respective toxin with an intact epoxy group and their acetylated derivatives. The cytotoxic effects was determined by using the 5-bromo-2'-deoxyuridine (BrdU) incorporation assay assessing DNA-synthesis. The toxicity of NIV and DON expressed as the concentration inhibiting 50% of the DNA synthesis (IC(50)), was occurring at similar micromolar concentrations (1.19+/-0.06 and 1.50+/-0.34 uM). The toxicity of fusarenon X (4-acetyl NIV) in the assay was similar to the toxicity of NIV, and the toxicity of 15-AcDON was equal to the toxicity of DON. 3-AcDON was less toxic than DON and 15-AcDON. The IC(50) value for de-epoxy DON was 54 times higher in the assay than the IC(50) for DON, while the IC(50) of de-epoxy NIV was 55 times higher than the IC(50) for NIV. The results verify previous findings that the de-epoxidation is a detoxification reaction.

来源:Hazardous Substances Data Bank (HSDB)

代谢

曲霉菌素是亲脂性的，因此能够轻易通过皮肤、肠道和肺粘膜被吸收。它们主要在肝脏通过细胞色素P-450和曲霉菌素特异性羧酸酯酶活性进行代谢，尽管其他组织，如肾脏、脾脏和肠道也表现出一些代谢活性。曲霉菌素通过水解、羟基化、去环氧化和葡萄糖苷酸化等反应，代谢转化为毒性较低的代谢物。硝酸萘酚的主要代谢物是去环氧硝酸萘酚。代谢物通过尿液和粪便排出体外。（L1910, L1949, A736）

Trichothecenes are lipophilic and thus easily absorbed through the skin, gut, and pulmonary mucosa. They are metabolized mainly by cytochrome P-450 and trichothecene-specific carboxylesterase activity in the liver, although other tissues such as the kidney, spleen, and intestine also show some metabolic activity. Trichothecenes are metabolically transformed to less toxic metabolites by such reactions as hydrolysis, hydroxylation, de-epoxidation, and glucuronidation. Nivalenol's major metabolite is de-epoxy nivalenol. Metabolites are excreted in the urine and feces. (L1910, L1949, A736)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

与许多其他真菌毒素不同，三环烯类不需要代谢激活就能发挥其生物活性，而是直接与细胞组分反应。三环烯类对大多数真核细胞具有细胞毒性，这是由于它们具有强大的抑制蛋白质合成能力。它们通过自由穿过质膜并特异性地与核糖体高亲和力结合来实现这一点。具体来说，它们干扰位于大28S核糖核酸3'端的多肽转移酶的活性位点，并抑制蛋白质合成的起始、延伸或终止步骤，以及导致多核糖体解聚。蛋白质合成是所有组织的基本功能，但在积极和快速生长和分裂的细胞组织中，对毒素非常敏感。此外，与核糖体的结合被认为会激活与免疫反应和凋亡相关的下游信号事件中的蛋白质，例如有丝分裂原活化蛋白激酶。这被称为核糖毒性应激反应。三环烯类还可能诱导一些膜结构的变化，导致脂质过氧化增加和线粒体中电子传递活性的抑制。它们还可以通过产生反应性氧种诱导凋亡。三环烯类的进一步次要效果包括抑制RNA和DNA合成，以及抑制有丝分裂。（L1948, L1949, A2962, A2963, A2964, A2980）

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)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌性证据

评估：对于禾谷镰刀菌产生的毒素在人类中的致癌性，目前证据不足。关于从F. crookwellense和F. culmorum产生的毒素对人类致癌性的数据并不存在。…在实验动物中，对于雪腐镰刀菌烯醇的致癌性证据也是不足的。…总体评估：来自禾谷镰刀菌、F. culmorum和F. crookwellense的毒素对人类致癌性无法分类（第3组）。

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 nivalenol. ... 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是一种多器官有毒物质，包括厌食和体重下降、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)

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

Nivalenol在小鼠体内迅速分布到所有检测的组织中，并且从这些组织中迅速消除，没有在任何器官中明显积累。

Nivalenol is rapidly distributed to and eliminated from all examined tissues in mice with no apparent accumulation in any organ.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

经过对雄性大鼠长期口服毒枝菌素后，剂量的回收情况如下：粪便中毒枝菌素（7%）、粪便中去环氧毒枝菌素（80%）、尿中毒枝菌素（1%）和尿中去环氧毒枝菌素（1%）。

After long term oral administration of nivalenol to male rats, the dose was recovered as fecal nivalenol (7%), fecal de-epoxy nivalenol (80%), urinary nivalenol (1%) and urinary de-epoxy nivalenol (1%).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

为了研究nivalenol（NIV）及其4-乙酰衍生物（fusarenon-X，FX）在小鼠体内的相对命运，将(3)H-FX或(3)H-NIV口服给小鼠。给予(3)H-FX的小鼠主要通过尿液排出放射性，而给予(3)H-NIV的小鼠则主要通过粪便排出。给予(3)H-FX或(3)H-NIV后，血浆中的放射性在30或60分钟达到峰值。血浆峰浓度是(3)H-FX给药小鼠的5倍，曲线下面积（AUC）是10倍。这些结果表明，FX比NIV更快速、更有效地从胃肠道吸收。尿液和粪便的乙腈提取物中放射性的HPLC图谱表明，FX在从胃肠道吸收后迅速代谢为NIV。将(3)H-FX与组织匀浆体外孵育表明，肝脏和肾脏是负责FX到NIV转化的器官。因此，这项研究表明，在小鼠和大鼠中观察到的FX比NIV的口服毒性更高，是由于FX比NIV更有效地从胃肠道吸收，随后被肝脏和肾脏迅速转化为NIV。

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. 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. 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.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)
• 危险品标志：
  Xn,T+,F
• 安全说明：
  S16,S22,S26,S28,S36/37,S36/37/39,S45
• 危险类别码：
  R26/27/28
• WGK Germany：
  3
• 海关编码：
  38220090
• 危险品运输编号：
  UN 2811 6
• 包装等级：
  I
• 危险类别：
  6.1(a)

制备方法与用途

生物活性

Nivalenol 是由禾谷镰刀菌 (Fusarium graminearum) 产生的 B 型三氯乙烯毒素 (B trichotecenes toxins)，是一种存在于农产品中的真菌代谢物。Nivalenol 通过依赖 caspase 的机制和内在的凋亡途径诱导细胞死亡，并影响免疫系统，导致呕吐、生长迟缓、生殖障碍以及血液毒性/骨髓毒性作用。

靶点

Caspase

文献信息

• IN VITRO METHOD FOR DETERMINING IMMUNOTOXICITY OF A COMPOUND
  申请人：Universiteit Maastricht

  公开号：EP3190414A1

  公开（公告）日：2017-07-12

  The invention is in the field of molecular diagnostics. More in particular it provides marker genes for determining the immunotoxicity of compounds. A method according to the invention employs samples obtained from a cell exposed to a potentially immunotoxic compound and determines expression levels of a number of marker genes in order to distinguish between immunotoxic compounds and non-immunotoxic compounds. More in particular, the invention relates to an in vitro method for determining whether a compound is immunotoxic wherein the expression level of at least one marker gene is determined in a sample obtained from a nucleated cell exposed to the compound, wherein the at least one marker gene is selected from the group consisting of ABCA1, CHAC1, CRIM1 and HMGCS1, and wherein it is concluded that the compound is immunotoxic if the expression level of said at least one marker gene is below or above a predetermined reference value.

  本发明属于分子诊断领域。尤其是它提供了用于确定化合物免疫毒性的标记基因。根据本发明的一种方法，利用从暴露于潜在免疫毒性化合物的细胞中获得的样本，确定一些标记基因的表达水平，以区分免疫毒性化合物和非免疫毒性化合物。更具体地说，本发明涉及一种确定化合物是否具有免疫毒性的体外方法，该方法测定从暴露于该化合物的有核细胞中获得的样品中至少一种标记基因的表达水平，其中至少一种标记基因选自 ABCA1、CHAC1、CRIM1 和 HMGCS1 所组成的组，如果所述至少一种标记基因的表达水平低于或高于预定参考值，则判定该化合物具有免疫毒性。
• Trichothecene-transforming alcohol dehydrogenase, method for transforming trichothecenes and trichothecene-transforming additive
  申请人：Erber Aktiengesellschaft

  公开号：US11001812B2

  公开（公告）日：2021-05-11

  An alcohol dehydrogenase of sequence ID numbers 2, 3 or 4 containing metal ions and a quinone cofactor, or in addition, a functional variant exhibiting a sequence identity of at least 80%, preferably at least 86%, especially preferred at least 89% and at least one redox cofactor for the transformation of at least one trichothecene exhibiting a hydroxyl group on the C-3 atom, as well as a method for the enzymatic transformation of trichothecenes and a trichothecene-transforming additive.

  一种序列 ID 号为 2、3 或 4 的醇脱氢酶，含有金属离子和醌辅助因子，或此外还含有一种功能变体，其序列同一性至少为 80%，优选至少为 86%，特别优选至少为 89%，并含有至少一种氧化还原辅助因子，用于转化至少一种 C-3 原子上带有羟基的单端孢霉烯，以及一种单端孢霉烯酶促转化方法和一种单端孢霉烯转化添加剂。
• In vitro method for determining immunotoxicity of a compound
  申请人：Universiteit Maastricht

  公开号：EP2708891B1

  公开（公告）日：2017-03-15
• VERWENDUNG EINER TRICHOTHECENE TRANSFORMIERENDEN ALKOHOLDEHYDROGENASE, VERFAHREN ZUR TRANSFORMATION VON TRICHOTHECENEN SOWIE TRICHOTHECENE TRANSFORMIERENDER ZUSATZSTOFF
  申请人：Erber Aktiengesellschaft

  公开号：EP3273802A1

  公开（公告）日：2018-01-31
• IMPROVED POLYPEPTIDES CAPABLE OF CONVERTING SUBSTRATE 3-KETO- DEOXYNIVALENOL INTO 3-EPI- DEOXYNIVALENOL
  申请人：Erber Aktiengesellschaft

  公开号：EP4022047A1

  公开（公告）日：2022-07-06