冈田(软海绵)酸 | 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
• 中文名称: 冈田(软海绵)酸
• 中文别名: 冈田酸；黑海棉酸
• 英文名称: okadaic acid
• 英文别名: 9,10-deepithio-9,10-didehydroacanthifolicin；ocadaic acid；okadaic acd；OKA；OA；(2R)-3-[(2S,6R,8S,11R)-2-[(E,2R)-4-[(2S,2'R,4R,4aS,6R,8aR)-4-hydroxy-2-[(1S,3S)-1-hydroxy-3-[(2S,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: 805.016
• InChiKey: QNDVLZJODHBUFM-WFXQOWMNSA-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

食用了被海洋生物毒素软海绵酸（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。我们研究的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的比较代谢物轮廓。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的激活作用与OA的整体转化能力较弱相一致。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御细胞毒性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

四达酸通过与人重组细胞色素P450 3A4的孵化产生了四种代谢物。通过MS/MS实验以及使用每种代谢物94和133微克的1D和2D NMR方法，已经确定了四种代谢物中两种的结构。第三种代谢物的结构是通过氧化成已知结构的代谢物来确定的。与四达酸一样，这些代谢物是蛋白磷酸酶PP2A的抑制剂。尽管其中一种代谢物具有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

鉴定和使用：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，其摄入会诱导胃肠道症状，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类支气管上皮细胞中诱导DNA加合物的形成。动物研究：在小鼠口服OA 1 mg/kg/day 7天后，诱导了腹泻、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可以诱导细胞骨架结构和细胞间接触的紊乱，导致染色体丢失、凋亡、DNA损伤并抑制磷酸酶，提示其潜在的胚胎毒性。OA在不同物种中用作药理诱导的阿尔茨海默病模型。在大鼠海马内双侧微注射OA导致空间记忆障碍。与对照组相比，OA暴露组的贻贝Perna perna的血细胞中微核的频率显著更高。OA在仓鼠肾（BHK）细胞中诱导DNA加合物的形成，也在斑马鱼胚胎中诱导了DNA加合物的形成。生态毒性研究：将蓝贻贝Mytilus edulis和太平洋牡蛎Crassostrea gigas暴露于OA中，并测量了对DNA断裂的影响。与对照组相比，这两种细胞类型在两种物种中均观察到DNA断裂的显著增加。在较高的毒素浓度下，太平洋牡蛎的增加更为显著。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为敏感。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

作者们建立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，由于奥克迪酸（OA）显著抑制蛋白磷酸酶活性，导致微管破坏。奥克迪酸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亚单位的过磷酸化/积累以及微管的破坏被