(1S,2R,3S,10R,11S)-3,10,11-trihydroxy-2-(hydroxymethyl)-1,5-dimethylspiro[8-oxatricyclo[7.2.1.02,7]dodec-5-ene-12,2'-oxirane]-4-one | 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: (1S,2R,3S,10R,11S)-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-IVXSKODCSA-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)
• 颜色/状态：
  Crystals from methanol
• 蒸汽压力：
  6.89X10-13 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 7.33X10-16 atm-cu m/mole 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)

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. 僧面素被代谢成去环氧僧面素。

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，比较了脱环氧的尼伐诺尔（NIV）和脱环氧的脱氧尼伐诺尔（DON）与它们各自的完整环氧基毒素以及它们的乙酰化衍生物的细胞毒性。细胞毒性效果是通过5-溴-2'-脱氧尿嘧啶（BrdU）掺入法评估DNA合成来确定的。NIV和DON的毒性，以抑制50%的DNA合成浓度（IC50）表示，发生在类似的微摩尔浓度（1.19±0.06和1.50±0.34 uM）。在实验中，镰刀菌素X（4-乙酰-NIV）的毒性类似于NIV，而15-乙酰-DON的毒性等于DON。3-乙酰-DON的毒性低于DON和15-乙酰-DON。脱环氧的DON的IC50值在实验中比DON的IC50值高54倍，而脱环氧的NIV的IC50值比NIV的IC50值高55倍。结果表明，脱环氧是一种解毒反应，验证了先前的发现。

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)

毒理性

• 致癌性证据

评估：对于来自禾谷镰刀菌的毒素的人类致癌性，人类身上的证据不足。没有关于来自F. crookwellense和F. culmorum的毒素对人类致癌性的数据。...在实验动物中，对于雪腐镰刀菌烯醇的致癌性证据不足。...总体评估：来自禾谷镰刀菌、F. culmorum和F. crookwellense的毒素不能归类为对人类具有致癌性（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

• 相互作用

进行了一项饲养试验，以确定Fusarium poae提取物对肉鸡健康和性能的影响以及天然沸石可能的保护作用。F. poae提取物含有nivalenol、T-2毒素和diacetoxyscirpenol，当以i.p.方式给予大鼠时表现出高毒性。一日龄的肉鸡在28天内自由采食以下饮食：I组 - 对照；II组 - 0.5%沸石；III组 - F. poae提取物；IV组 - 0.5%沸石和F. poae提取物。在28天时宰杀肉鸡，以测量相对器官重量、白细胞计数和血清生化值。实验期间没有记录到死亡。F. poae提取物抑制了体重增加、饲料摄入量、饲料利用率和饮水量（p<0.05）。在接受沸石和F. poae提取物饮食的IV组中也观察到了这些参数的下降。与对照组相比，II组没有显著差异。在III组和IV组中，肝脏、肾脏、心脏和肌胃的相对重量显著增加（p<0.05），而在II组中只有相对肝脏重量增加。单独或与沸石联合给予的F. poae提取物显著降低了白细胞计数、血清总蛋白和血清白蛋白。沸石和F. poae提取物，单独或联合使用，增加了血清肌酐和尿酸浓度（p<0.05）。这些发现表明，亚致死剂量的F. poae提取物可能会对肉鸡的性能和健康产生不利影响。添加沸石后，这些损害并未减少，对于某些参数，沸石添加剂增加了F. poae提取物的有害影响。

A feeding trial was conducted in order to determine the effects of a Fusarium poae extract on the health and performances of broiler chickens and the possible protective effect of a natural zeolite. The F. poae extract contained nivalenol, T-2 toxin and diacetoxyscirpenol and demonstrated high toxicity when administered i.p. to rats. One-day-old broiler chickens were fed ad libitum over a period of 28 days with the following diets: group I - control; group II - 0.5% zeolite; group III -F. poae extract; group IV-0.5% zeolite andF. poae extract. Broilers were sacrificed at 28 days for the measurement of relative organs weights, leukocyte counts and serum biochemical values. No mortality was recorded over the experiment. Body weight gains, feed intake, feed utilization and water consumption were depressed by the F. poae extract (p<0.05). A decrease of these parameters was also observed in group IV which received the diet with zeolite and the F. poae extract. No significant differences were seen in group II when compared to control. In groups III and IV the relative weights of liver, kidney, heart and gizzard were significantly increased (p<0.05), while in group II only the relative liver weight was increased. F. poae extract, administered singly or in combination with zeolite, significantly decreased leukocytes count, serum total protein and serum albumin. Zeolite and F. poae extract, singly or combined, increased serum creatinine and uric acid concentrations (p<0.05). These findings indicate that sublethal doses of F. poae extract can affect adversely the performances and the health in broiler chickens. By adding zeolite these impairments could not be diminished and for some parameters the zeolite additive increased the adverse effects of the F. poae extract.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

脱氧雪腐镰刀菌烯醇（DON）和雪腐镰刀菌烯醇（NIV）是经常在谷物中同时出现的有毒 Fusarium 次级三线镰孢霉代谢物。本研究比较了这两种化合物对 C57BL/6 小鼠的毒性，包括血浆生化变化、免疫系统反应性和肝脏药物代谢能力等多个参数。小鼠以单独或联合口服的方式接受每种毒素：每千克体重 0.071 毫克或 0.355 毫克，每周三次，持续 4 周。NIV 单独给药 0.355 毫克/千克体重时，食物消耗量发生了改变，尽管没有检测到体重、器官重量或肝脏蛋白质含量的显著变化。NIV 给药还导致血浆中总 CO2 和尿酸浓度显著变化。单独毒素暴露导致血浆 IgA 增加，而脾细胞产生的细胞因子没有明显变化。肝脏 ethoxyresorufin O-脱烷基酶、pentoxyresorufin O-脱戊基酶和谷胱甘肽 S-转移酶活性增加，同时细胞色素 P4501a 和 P4502b 亚家族表达也增加。DON 和 NIV 的联合给药产生的反应与单独使用每种毒素的反应相似。然而，根据毒素剂量比和生化参数的不同，一些反应可能是加性的（血浆 IgA 和肝脏 DCNB 结合）或者是协同的（血浆尿酸）。

Deoxynivalenol (DON) and nivalenol (NIV) are toxic Fusarium secondary trichothecene metabolites that often co-occur regularly in cereal grains. These compounds were compared for their toxicity towards C57BL/6 mice on several parameters including alteration in plasma biochemistry, immune system reactivity and hepatic drug metabolism capacity. Mice received individual or combined oral doses of each toxin: 0.071 or 0.355 mg/kg of body weight, administrated three days a week for 4 weeks. Food consumption was altered by the single administration of 0.355 mg/kg of NIV, although no noticeable change of body and organ weights or liver protein contents was detected. NIV administration did cause also significant changes in total CO2 and uric acid concentrations in plasma. Individual toxin exposures led to increases in plasma IgA without no detectable change in the ex vivo production of cytokine by splenocytes. The liver ethoxyresorufin O-deealkylase, pentoxyresorufin O-depenthylase and glutathione S-transferase activities were increased in concert with cytochrome P4501a and P4502b subfamily expression. Administration of combinations of DON and NIV resulted in responses similar to that observed using individual doses of each toxin. However, depending on the ratio of toxin doses and biochemical parameters, some responses could be also additive (plasma IgA and hepatic DCNB conjugation) or synergistic (plasma uric acid).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

脱氧雪腐镰刀菌烯醇（DON）是欧洲和北美作物中最普遍的镰刀菌毒素。DON经常与其他B型镰刀菌毒素如3-乙酰脱氧雪腐镰刀菌烯醇（3-ADON）、15-乙酰脱氧雪腐镰刀菌烯醇（15-ADON）、雪腐镰刀菌烯醇（NIV）和镰刀菌素-X（FX）一起存在。尽管单个真菌毒素的细胞毒性已经被广泛研究，但关于真菌毒素混合物的毒性的数据有限。这项研究的目的是评估B型镰刀菌毒素共同暴露对肠道上皮细胞的影响。将增殖的Caco-2细胞暴露于不断增加剂量的B型镰刀菌毒素，单独使用或以二种或三种混合物形式使用。使用MTT试验和中性红摄取，分别与线粒体和溶酶体功能相关，来测量肠道上皮细胞毒性。五种测试的真菌毒素对增殖的肠细胞有剂量依赖性的影响，并且可以按照毒性增加的顺序进行分类：3-ADON<15-ADON =~ DON<NIV << FX。二种或三种混合物也显示出剂量依赖性的效果。在低浓度下（细胞毒性效应在10%到30-40%之间），真菌毒素组合显示出协同作用；然而，DON-NIV-FX混合物显示出拮抗作用。在高浓度下（细胞毒性效应约为50%），组合物具有相加或几乎相加的效果。这些结果表明，食品商品和饮食中同时存在低剂量的真菌毒素可能比单独的真菌毒素预测的毒性更大。考虑到饮食中镰刀菌毒素的频繁共现以及消费者接触到的毒素浓度，这种协同作用应该被考虑在内。

Deoxynivalenol (DON) is the most prevalent trichothecene mycotoxin in crops in Europe and North America. DON is often present with other type B trichothecenes such as 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), nivalenol (NIV) and fusarenon-X (FX). Although the cytotoxicity of individual mycotoxins has been widely studied, data on the toxicity of mycotoxin mixtures are limited. The aim of this study was to assess interactions caused by co-exposure to Type B trichothecenes on intestinal epithelial cells. Proliferating Caco-2 cells were exposed to increasing doses of Type B trichothecenes, alone or in binary or ternary mixtures. The MTT test and neutral red uptake, respectively linked to mitochondrial and lysosomal functions, were used to measure intestinal epithelial cytotoxicity. The five tested mycotoxins had a dose-dependent effect on proliferating enterocytes and could be classified in increasing order of toxicity: 3-ADON<15-ADON =~ DON<NIV << FX. Binary or ternary mixtures also showed a dose-dependent effect. At low concentrations (cytotoxic effect between 10 and 30-40%), mycotoxin combinations were synergistic; however DON-NIV-FX mixture showed antagonism. At higher concentrations (cytotoxic effect around 50%), the combinations had an additive or nearly additive effect. These results indicate that the simultaneous presence of low doses of mycotoxins in food commodities and diet may be more toxic than predicted from the mycotoxins alone. Considering the frequent co-occurrence of trichothecenes in the diet and the concentrations of toxins to which consumers are exposed, this synergy should be taken into account.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

含有霉菌毒素的大麦被纳入了产蛋鸡的饮食中，以研究对性能和健康的影响。健康指标是不同的血液血浆参数和肝脏维生素A和E水平。共有30只鸡被喂食3种饮食，其中一种补充了30%的无毒素大麦，另外两种分别添加了1997年和1998年不同发霉的大麦，持续7周。发霉的饮食中含有低到中等浓度的赭曲霉毒素A、玉米赤霉烯酮、脱氧雪腐镰刀菌烯醇和雪腐镰刀菌醇。在饮食中加入发霉的大麦对饲料摄入量、饲料转化率、营养物质的消化率、产蛋率和蛋品质产生了不利影响。血浆碱性磷酸酶增加，某些生化血液参数（胆红素、尿酸、氯化物、蛋白质、白蛋白、维生素A）也高于或与对照组相比有所变化。尽管赭曲霉毒素A的污染相对较低，但它可能对其中一些效果以及饲料摄入量的减少有所贡献。更高的霉菌污染以及含有1998年大麦的饮食中的一种未知的细胞毒性成分可能也能解释这种饮食带来的更明显的影响。

Molded and mycotoxin containing barley was incorporated into the diets for laying hens to study the effects on performance and health. Health indicators were different blood plasma parameters and liver vitamin A and E levels. A total of 30 hens were fed 3 diets, one supplemented with 30% of toxin-free and two with differently molded barley from 1997 and 1998 for 7 weeks. The molded diets contained low to moderate concentrations of ochratoxin A, zearalenone, deoxynivalenol and nivalenol. Inclusion of moldy barley in the diets had an adverse effect on feed intake, feed conversion, digestibility of nutrients, egg production and egg quality. Plasma alkaline phosphatase was increased and certain biochemical blood parameters (bilirubin, uric acid, chloride, protein, albumin, vitamin A) were also higher or changed compared to control. The ochratoxin A contamination although relatively low could have contributed to some of these effects as well as reduced intake of feed. The higher mold contamination and an unidentified cell-toxic constituent in the diet containing barley from 1998 can probably also explain the more marked effects from this diet.

来源:Hazardous Substances Data Bank (HSDB)

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