(2R)-3-[(2S,6R,8S,11R)-2-[(E)-4-[(2R,4R,4aS,6R,8aR)-4-hydroxy-2-[(1S,3S)-1-hydroxy-3-[(2R,3R,6S)-3-methyl-1,7-dioxaspiro[5.5]undecan-2-yl]butyl]-3-methylidenespiro[4a,7,8,8a-tetrahydro-4H-pyrano[3,2-b]pyran-6,5'-oxolane]-2'-yl]but-3-en-2-yl]-11-hydroxy-4-methyl-1,7-dioxaspiro[5.5]undec-4-en-8-yl]-2-hydroxy-2-methylpropanoic acid | 78111-17-8

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2R)-3-[(2S,6R,8S,11R)-2-[(E)-4-[(2R,4R,4aS,6R,8aR)-4-hydroxy-2-[(1S,3S)-1-hydroxy-3-[(2R,3R,6S)-3-methyl-1,7-dioxaspiro[5.5]undecan-2-yl]butyl]-3-methylidenespiro[4a,7,8,8a-tetrahydro-4H-pyrano[3,2-b]pyran-6,5'-oxolane]-2'-yl]but-3-en-2-yl]-11-hydroxy-4-methyl-1,7-dioxaspiro[5.5]undec-4-en-8-yl]-2-hydroxy-2-methylpropanoic acid
• CAS: 78111-17-8
• 化学式: C₄₄H₆₈O₁₃
• 分子量: 805.0
• InChiKey: QNDVLZJODHBUFM-ZJOMISMMSA-N

物化性质

• 熔点：
  164-166 °C
• 比旋光度：
  D20 +21° (c = 0.33 in CHCl3); D25 +25.4° (c = 0.24 in CHCl3)
• 沸点：
  672.95°C (rough estimate)
• 密度：
  1.0795 (rough estimate)
• 溶解度：
  二甲基亚砜：≥1 mg/mL
• 颜色/状态：
  Crystals from dichloromethane/hexane; crystals from benzene-CHCl3
• 稳定性/保质期：
  Stable under recommended storage conditions.
• 旋光度：
  Specific optical rotation = +21 deg at 20 °C/D (c = 0.33 in CHCl3); +25.4 deg at 25 °C/D (c = 0.24 in CHCl3)
• 分解：
  Hazardous decomposition products formed under fire conditions. - Carbon oxides

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  57
• 可旋转键数：
  10
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  183
• 氢给体数：
  5
• 氢受体数：
  13

ADMET

代谢

摄入被海洋生物毒素(okadaic acid, OA)污染的海鲜可能导致腹泻性贝类中毒，症状包括恶心、呕吐和腹痛。大鼠和人类的肝脏细胞色素P450单加氧酶（CYP）都能代谢OA。然而，代谢后的OA对肝细胞的毒性尚不清楚。我们的研究目的是检测在加入大鼠和人类重组CYP酶的情况下，HepG2细胞暴露于OA时的细胞效应，以研究物种差异。结果应与CYP特异性代谢物模式相关联。通过使用LC-MS/MS技术，建立了在大鼠和人类重组CYP酶中孵育后OA的比较代谢物谱。结果表明，OA代谢为氧化代谢物与解毒作用相关，主要由人类CYP3A4和CYP3A5催化。与人类CYP3A酶相比，大鼠Cyp3a1的解毒作用较低，而Cyp3a2对OA的活化作用与OA的整体转化能力较弱相符。相比之下，人类和大鼠CYP1A2似乎将OA激活为细胞毒性中间体。总之，肝脏中可能发生不同的OA代谢机制。在低剂量的OA情况下，人类肝脏可能很好地抵抗细胞毒性OA，但对于大量食用贝类的消费者，不能排除潜在风险。

The ingestion of seafood contaminated with the marine biotoxin okadaic acid (OA) can lead to diarrhetic shellfish poisoning with symptoms like nausea, vomiting and abdominal cramps. Both rat and the human hepatic cytochrome P450 monooxygenases (CYP) metabolize OA. However, liver cell toxicity of metabolized OA is mainly unclear. The aim of our study was to detect the cellular effects in HepG2 cells exposed to OA in the presence of recombinant CYP enzymes of both rat and human for the investigation of species differences. The results should be set in correlation with a CYP-specific metabolite pattern. Comparative metabolite profiles of OA after incubation in rat and human recombinant CYP enzymes were established by using LC-MS/MS technique. Results demonstrated that metabolism of OA to oxygenated metabolites correlates with detoxification which was mainly catalyzed by human CYP3A4 and CYP3A5. Detoxification by rat Cyp3a1 was lower compared to human CYP3A enzymes and activation of OA by Cyp3a2 was observed, coincident with minor overall conversion capacity of OA. By contrast human and rat CYP1A2 seem to activate OA into cytotoxic intermediates. In conclusion, different mechanisms of OA metabolism may occur in the liver. At low OA doses, the human liver is likely well protected against cytotoxic OA, but for high shellfish consumers a potential risk cannot be excluded.

来源:Hazardous Substances Data Bank (HSDB)

代谢

通过与人类重组细胞色素P450 3A4的孵化，产生了四个奥克迪酸的代谢物。通过MS/MS实验以及使用每个代谢物94和133微克的1D和2D NMR方法，已经确定了四个代谢物中两个的结构。第三个代谢物的结构是通过氧化成已知结构的代谢物而确定的。与奥克迪酸一样，这些代谢物是蛋白磷酸酶PP2A的抑制剂。尽管其中一个代谢物具有alpha,beta不饱和羰基，有可能与活性位点的半胱氨酸形成加合物，但所有代谢物都是PP2A的可逆抑制剂。

Four metabolites of okadaic acid were generated by incubation with human recombinant cytochrome P450 3A4. The structures of two of the four metabolites have been determined by MS/MS experiments and 1D and 2D NMR methods using 94 and 133 ug of each metabolite. The structure of a third metabolite was determined by oxidation to a metabolite of known structure. Like okadaic acid, the metabolites are inhibitors of protein phosphatase PP2A. Although one of the metabolites does have an alpha,beta unsaturated carbonyl with the potential to form adducts with an active site cysteine, all of the metabolites are reversible inhibitors of PP2A.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：岗田酸（OA）是一种固体。OA 是最常见且全球分布的海洋毒素之一。它容易被贝类动物积累，主要是双壳类软体动物和鱼类，随后可能被人类食用，导致食物中毒。OA 作为一种生化工具，用作肿瘤促进剂和细胞调控探针。人体研究：OA 是主要的腹泻性贝类中毒（DSP）毒素，其摄入会导致胃肠道症状，尽管它并不被认为是致命的。在分子水平上，OA 是几种丝氨酸/苏氨酸蛋白磷酸酶的特异性抑制剂。OA 在人角质形成细胞和人支气管上皮细胞中诱导 DNA 加合物。动物研究：在小鼠口服 1 毫克/千克/天的 OA 7 天后，引起了腹泻、体重减轻、食物摄入量减少和死亡。OA 在小鼠皮肤的二阶段实验中是一种肿瘤促进剂。OA 可导致细胞骨架结构和细胞间接触的紊乱，引起染色体丢失、凋亡、DNA 损伤并抑制磷酸酶，这表明其潜在的胚胎毒性。OA 在不同物种中用作阿尔茨海默病的药理学诱导模型。在大鼠海马内双侧微注射 OA 导致空间记忆受损。与对照相比，从暴露于 OA 的小组贻贝 Perna perna 中观察到的微核频率显著较高。OA 在仓鼠肾（BHK）细胞中诱导 DNA 加合物的形成，也在斑马鱼胚胎中证明了 DNA 加合物的诱导。生态毒性研究：蓝贻贝 Mytilus edulis 和太平洋牡蛎 Crassostrea gigas 在体内暴露于 OA，并测量了对 DNA 断裂的影响。与对照组相比，两种细胞类型的两种物种都观察到了显著的 DNA 断裂增加。在较高的毒素浓度下，这种增加在太平洋牡蛎中更为显著。在贻贝 Mytilus galloprovincialis 中，贻贝鳃细胞对 OA 介导的早期遗传毒性比血细胞更敏感。在玉米细胞中，OA 导致细胞周期在前期停滞，导致幼苗生长抑制。

IDENTIFICATION AND USE: Okadaic acid (OA) is a solid. OA is one of the most frequent and worldwide distributed marine toxins. It is easily accumulated by shellfish, mainly bivalve mollusks and fish, and, subsequently, can be consumed by humans causing alimentary intoxications. OA is used as a biochemical tool as tumor promoter and probe of cellular regulation. HUMAN STUDIES: OA is the main representative diarrheic shellfish poisoning (DSP) toxin and its ingestion induces gastrointestinal symptoms, although it is not considered lethal. At the molecular level, OA is a specific inhibitor of several types of serine/threonine protein phosphatases. Induction of DNA adducts by OA was shown in human keratinocytes and human bronchial epithelial cells. ANIMAL STUDIES: In mice after 7 days of oral administration of 1 mg/kg/day OA induced diarrhea, body weight loss, reduced food consumption, and death. OA was a tumor promoter in two-stage experiments on mouse skin. OA can induce disorganization in cytoskeletal architecture and cell-cell contact, cause chromosome loss, apoptosis, DNA damage and inhibit phosphatases, suggesting its potential embryotoxicity. OA is used as a pharmacologically induced model of Alzheimer's disease in different species. In rats intrahippocampal bilateral microinjection of OA led to a spatial memory impairment. A significantly higher frequency of micronuclei was observed in hemocytes from the OA-exposed group of the mussel Perna perna compared to control. Induction of DNA adducts by OA was shown in Baby Hamster Kidney (BHK) cells, also the induction of DNA adducts in zebra fish embryos was demonstrated. ECOTOXICITY STUDIES: The blue mussel, Mytilus edulis and the pacific oyster, Crassostrea gigas were exposed in vivo to OA and impacts on DNA fragmentation were measured. A significant increase in DNA fragmentation was observed in the two cell types from both species relative to the controls. This increase was greater in the pacific oyster at the higher toxin concentration. In mussel Mytilus galloprovincialis mussel gill cells display higher sensitivity to early OA-mediated genotoxicity than hemocytes. In maize cells, OA caused the cell cycle arrest at preprophase, leading to seedling growth inhibition.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

作者们构建了一个神经母细胞瘤（SH-SY5Y）细胞系，其中细胞骨架蛋白异常磷酸化，由于奥克酸（OA）显著抑制蛋白磷酸酶活性，导致微管破坏。OA诱导的细胞活性和线粒体代谢活动的下降被褪黑素显著预防。此外，由OA诱导的神经丝（NF-）H/M亚单位的过度磷酸化/积累以及微管的破坏也被褪黑素显著抑制。

/The authors/ generated a neuroblastoma (SH-SY5Y) cell system in which cytoskeletal proteins are abnormally phosphorylated resulting in microtubule disruption due to the marked inhibition of protein phosphatase activities by okadaic acid (OA). OA-induced declines in cell viability and mitochondrial metabolic activity were remarkably prevented by melatonin. In addition, the hyperphosphorylation/accumulation of neurofilament-(NF-) H/M subunits and the disruption of microtubules, induced by OA, were significantly inhibited by melatonin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在大鼠清醒状态下，向海马内微量注射奥卡酸（一种强效的蛋白磷酸酶1和2A的抑制剂），在大约20分钟内会引发强烈的脑电图和行为上的边缘型癫痫发作，这种发作可以通过系统给予NMDA受体拮抗剂（+）-5-甲基-10,11-二氢-5H-二苯并-[a,d]环庚烯-5,10-亚胺氢雄酸盐以及海马内注射1-(5-异喹啉磺酰基)-2-甲基哌嗪（一种蛋白激酶的抑制剂）来抑制。

In awake rats the microinjection into the hippocampus of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A, induces in about 20 min intense electroencephalographic and behavioral limbic-type seizures, which are suppressed by the systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine hydrogen maleate and by the intrahippocampal administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, an inhibitor of protein kinases.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

奥卡地酸（OA）是一种海洋毒素，也是一种肿瘤促进剂和凋亡诱导剂。它主要抑制蛋白磷酸酶、蛋白质合成并增强脂质过氧化。将Caco-2细胞分别仅用OA（15 ng/mL）或镉（Cd）（0.625和5 ug/mL）处理24小时，蛋白质合成受到抑制（分别抑制了42 +/- 5%，18 +/- 13%，和90 +/- 4%），而丙二醛（MDA）的产生分别是2,235 +/- 129, 1,710 +/- 20, 和11,496 +/-1,624 pmol/mg蛋白质。此外，每种毒素都在DNA中诱导了修饰碱基的增加；氧化碱基和甲基化dC的增加。OA和镉的组合更具细胞毒性，并导致更多的DNA碱基修饰；m(5)dC/(m(5)dC + dC)的比例从3 +/- 0.15增加到9 +/- 0.15，而8-(OH)-dG/10(5) dG的比例也从36 +/- 2增加到76 +/- 6。OA和Cd的组合也增加了MDA的水平（16,874 +/- 2,189 pmole/mg蛋白质）。当前结果强烈表明，由这两种毒素引起的氧化应激导致的DNA损伤可能通过表观遗传过程显著增加其致癌性。

Okadaic acid (OA) is a marine toxin, a tumor promoter and an inducer of apoptosis. It mainly inhibits protein-phosphatases, protein synthesis and enhances lipid peroxidation. Caco-2 cells were treated exclusively by OA (15 ng/mL) or cadmium (Cd) (0.625 and 5 ug/mL) for 24 hr, protein synthesis was inhibited (by 42 +/- 5%, 18 +/- 13%, and 90 +/- 4% respectively) while /malondialdehyde/ (MDA) production was 2,235 +/- 129, 1710 +/- 20, and 11,496 +/-1,624 pmol/mg protein respectively. In addition, each toxicant induced modified bases in DNA; increases in oxidised bases and methylated dC. The combination of OA and cadmium was more cytotoxic and caused more DNA base modifications; the ratio m(5)dC/(m(5)dC + dC) was increased from 3 +/- 0.15 to 9 +/- 0.15 and the ratio 8-(OH)-dG/10(5) dG also (from 36 +/- 2 to 76 +/- 6). The combination of OA and Cd also increased the level of MDA (1,6874 +/- 2,189 pmole/mg protein). The present results strongly suggest that DNA damage resulting from the oxidative stress induced by these two toxicants may significantly contribute to increasing their carcinogenicity via epigenetic processes.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

25纳摩尔奥克达酸能促进B16黑素瘤的DNA断裂，增加细胞脱落以及色素沉着，这是黑素细胞分化的特征。在较低水平时，奥克达酸与紫外线暴露协同作用，增加DNA断裂。

25 nM okadaic acid promotes DNA fragmentation in B16 melanoma, increasing cell detachment as well as pigmentation, a characteristic of melanocytic cell differentiation. At lower levels, okadaic acid synergizes with UV exposure to increase DNA fragmentation.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

这项研究的结果显示...这种海洋毒素能够穿越胎盘屏障。胎儿组织中的冈田酸含量比肝脏或肾脏要高：通过高效液相色谱（HPLC）和9-蒽基重氮甲烷（ADAM）衍生化后的荧光检测，测量值为5.60%，而肝脏和肾脏分别为1.90%和2.55%。

The results in this study show... that this marine toxin is able to cross the transplacental barrier. Fetal tissue contains more okadaic acid than the liver or kidney: 5.60% compared to 1.90 and 2.55% respectively as measured by HPLC and fluorescent detection after derivatization with 9-Anthryldiazomethane (ADAM).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

这项研究涉及3H-软海绵酸（OA）在瑞士小鼠的单次口服OA（50微克/千克）后器官和生物流体中的分布。给药后24小时对肠组织和内容物的测定表明OA的消除缓慢。当OA剂量从50-90微克/千克增加时，肠内容物和粪便中毒素的浓度相应增加。在口服90微克/千克的动物中，肠组织中OA的增加与腹泻之间存在良好的相关性。此外，OA存在于肝脏和胆汁以及包括皮肤在内的所有器官和流体中。总的来说，这些结果证实了OA的肠肝循环，之前的研究已经显示过这一点。

This study concerns the distribution of 3H-okadaic acid (OA) in organs and biological fluids of Swiss mice having received a single dose per os of OA (50 ug/kg). The determination of the intestinal tissues and contents 24 hr after administration demonstrates a slow elimination of OA. When the dose of OA was increased from 50-90 ug/kg, the concentrations of the toxin in the intestinal content and feces increased proportionally. A good correlation was found between an increase of OA in the intestinal tissue and the diarrhea in animals given 90 ug/kg orally. Moreover OA was present in liver and bile and in all organs including skin and also fluids. Altogether these results confirmed an enterohepatic circulation of OA as previously shown.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

营养制度和温度对砗磲OA组毒素的净化率影响的研究，通过将自然污染的标本暴露在三种营养制度（微藻、微藻的商业糊状物和饥饿）下，持续14天，温度为16°C和20°C。在实验的第2、4、6、8、10、12和14天收集的个体的整个软组织中定量总OA。调查了死亡率、干重、状况指数、总生化组成和生殖阶段。实验中肝糖原和碳水化合物的低变化表明砗磲处于非剧烈压力条件下。喂食无毒饮食的砗磲显示出相似的净化率，比饥饿条件下分别高出15%和38%，在16°C和20°C下。在20°C下无毒饮食的净化率比16°C高出71%。这些结果突出了水温对砗磲积累的总OA净化率的影响，即使温度只增加了4°C，这在葡萄牙南部沿海水域的周时间尺度上常见。这些结果表明，当水温略有升高时，转移到净化系统的收获砗磲可能会更快地释放OA。

The influence of nutritional regime and water temperature on depuration rates of OA-group toxins in the wedge shell Donax trunculus was examined by exposing naturally contaminated specimens to three nutritional regimes (microalgae, commercial paste of microalgae, and starvation) for 14 days at 16 °C and 20 °C. Total OA was quantified in the whole soft tissues of the individuals collected in days 2, 4, 6, 8, 10, 12 and 14. Mortality, dry weight, condition index, gross biochemical composition and gametogenic stages were surveyed. Low variation of glycogen and carbohydrates during the experiments suggest that wedge shells were under non-dramatic stress conditions. Wedge shells fed with non-toxic diets showed similar depuration rates being 15 and 38% higher than in starvation, at 16 and 20 °C, respectively. Depuration rates under non-toxic diets at 20 °C were 71% higher than at 16 °C. These results highlight the influence of water temperature on the depuration rate of total OA accumulated by D. trunculus, even when the increase is of only 4 °C, as commonly observed in week time scales in the southern Portuguese coastal waters. These results open the possibility of a faster release of OA in harvested wedge shells translocated to depuration systems when under a slight increase of water temperature.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

酸性毒素，包括岗田酸（OA）及其衍生物双鞭藻毒素（DTXs）。OA及其衍生物（DTX1、DTX2和DTX3）是脂溶性的，会在贝类脂肪组织中积累。这些化合物是强效磷酸酶抑制剂，这一特性与人类的肠道炎症和腹泻有关。

... acidic toxins, include okadaic acid (OA) and its derivatives named dinophysistoxins (DTXs). OA and its derivatives (DTX1, DTX2 and DTX3) are lipophilic and accumulate in the fatty tissue of shellfish. These compounds are potent phosphatase inhibitors and this property is linked to inflammation of the intestinal tract and diarrhea in humans.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

奥克迪酸被认为是一种腹泻性贝类毒素。目前认为，奥克迪酸被吸收进入人体后，没有特定的靶器官。然而，其药代动力学的细节仍然未知。在本研究中，我们证明了奥克迪酸对表达肝细胞特异性摄取转运体OATP1B1或OATP1B3的细胞比对转染了控制载体的细胞毒性更大。此外，奥克迪酸抑制了其靶分子PP2A的活性，在表达OATP1B1或OATP1B3的细胞中，这种抑制作用比在转染了控制载体的细胞中更为显著。奥克迪酸在表达OATP1B1或OATP1B3的细胞中的细胞毒性可以通过已知的OATP1B1和OATP1B3的底物来减轻，但在转染了控制载体的细胞中则不然。此外，在使用表达OATP1B3的细胞进行的摄取抑制研究中，Dixon图显示奥克迪酸以竞争性方式抑制了肝毒素微囊藻毒素-LR的摄取，微囊藻毒素-LR是OATP1B1和OATP1B3的底物。这些结果强烈表明奥克迪酸是OATP1B3的底物，也可能是OATP1B1的底物，并可能涉及未知的导致肝衰竭和肝癌的原因。由于奥克迪酸具有通过其已知的磷酸酶抑制活性而产生的细胞毒性和细胞增殖活性。

Okadaic acid is known as a diarrheal shellfish poison. It is thought that there is no specific target organ for okadaic acid after it has been absorbed into the body. However, the details of its pharmacokinetics are still unknown. In this study, we demonstrated that okadaic acid was more toxic to the hepatocyte-specific uptake transporter OATP1B1- or OATP1B3-expressing cells than control vector-transfected cells. In addition, PP2A activity, which is a target molecule of okadaic acid, was more potently inhibited by okadaic acid in OATP1B1- or OATP1B3-expressing cells compared with control vector-transfected cells. The cytotoxicity of okadaic acid in OATP1B1- or OATP1B3-expressing cells was attenuated by known substrates of OATP1B1- and OATP1B3, but not in control vector-transfected cells. Furthermore, after uptake inhibition study using OATP1B3-expressing cells, Dixon plot showed that okadaic acid inhibited the uptake of hepatotoxin microcystin-LR, which is a substrate for OATP1B1 and OATP1B3, in a competitive manner. These results strongly suggested that okadaic acid is a substrate for OATP1B3 and probably for OATP1B1, and could be involved in unknown caused liver failure and liver cancer. Since okadaic acid possesses cytotoxicity and cell proliferative activity by virtue of its known phosphatase inhibition activity.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)
• 危险品标志：
  T
• 危险类别码：
  R23/24/25
• 危险品运输编号：
  UN 3462 6
• WGK Germany：
  3
• RTECS号：
  AA8227800
• 包装等级：
  II
• 危险类别：
  6.1(a)
• 危险标志：
  GHS06
• 危险性描述：
  H301,H311,H315,H331
• 危险性防范说明：
  P261,P280,P301 + P310,P311

制备方法与用途

生物活性

Okadaic acid 是从 Halichondria 属的黑色海绵中提取的一种非竞争性、选择性和可逆性的丝氨酸/苏氨酸特异性蛋白磷酸酶 1 (PP1)、PP2A 和 PP3 的抑制剂，其 IC50 值分别为 10-15 nM、0.5 nM 和 4 nM。Okadaic acid 能通过诱导细胞凋亡消除后生共生体/寄生虫。

靶点

• IC50: 10-15 nM (PP1), 0.5 nM (PP2) and 4 nM (PP3)

类别

有毒物品

毒性分级

剧毒

急性毒性

腹腔注射 - 小鼠 LD50: 0.192 毫克/公斤

可燃性危险特性

可燃，火场排出辛辣刺激烟雾

储运特性

库房低温、通风、干燥；与食品原料分开存放

灭火剂

水、二氧化碳、干粉、砂土