α-punicalagin

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 单宁
• 英文名称: α-punicalagin
• 英文别名: punicalagin α；(1R,35R,37S,38R,55S)-6,7,8,11,12,23,24,27,28,29,37,43,44,45,48,49,50-heptadecahydroxy-2,14,21,33,36,39,54-heptaoxaundecacyclo[33.20.0.04,9.010,19.013,18.016,25.017,22.026,31.038,55.041,46.047,52]pentapentaconta-4,6,8,10,12,16,18,22,24,26,28,30,41,43,45,47,49,51-octadecaene-3,15,20,32,40,53-hexone
• 化学式: C₄₈H₂₈O₃₀
• 分子量: 1084.73
• InChiKey: ZJVUMAFASBFUBG-OGJBWQGYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  78
• 可旋转键数：
  0
• 环数：
  11.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  511
• 氢给体数：
  17
• 氢受体数：
  30

ADMET

代谢

石榴，一种原产于中东的水果，已经作为一种功能食品和营养保健源在全球范围内获得了广泛的流行。整果以及其果汁和提取物的健康效果已经针对多种慢性疾病进行了研究。来自人类临床试验的数据显示，石榴对心血管疾病、糖尿病和前列腺癌具有积极效果。石榴的体外抗氧化活性归功于其高含量的多酚类化合物，特别是石榴酸、石榴素、没食子酸和鞣花酸。这些化合物在消化过程中被代谢为鞣花酸和尿石素，这表明提供体内抗氧化活性的生物活性化合物可能与完整食物中存在的化合物不同……

Pomegranate, a fruit native to the Middle East, has gained widespread popularity as a functional food and nutraceutical source. The health effects of the whole fruit, as well as its juices and extracts, have been studied in relation to a variety of chronic diseases. Promising results against cardiovascular disease, diabetes, and prostate cancer have been reported from human clinical trials. The in vitro antioxidant activity of pomegranate has been attributed to its high polyphenolic content, specifically punicalagins, punicalins, gallagic acid, and ellagic acid. These compounds are metabolized during digestion to ellagic acid and urolithins, suggesting that the bioactive compounds that provide in vivo antioxidant activity may not be the same as those present in the whole food...

来源:Hazardous Substances Data Bank (HSDB)

代谢

石榴已经显示出含有124种不同的植物化学物质，其中一些共同作用，对癌细胞发挥抗氧化和抗炎效果。鞣花酸是石榴中存在的生物活性多酚。通过压榨整个水果获得的石榴汁比任何常见饮用的果汁含有更高的鞣花酸浓度，并且含有独特的鞣花酸，即石榴鞣花酸。石榴鞣花酸是已知分子量最大的多酚。石榴鞣花酸不会完整地被血液吸收，而是在小肠中经过数小时水解成鞣花酸。鞣花酸也被肠道菌群代谢成尿石酸，这些尿石酸在肝脏结合后通过尿液排出。这些尿石酸也具有生物活性，并能抑制前列腺癌细胞的生长...

Pomegranates have been shown to contain 124 different phytochemicals, and some of them act in concert to exert antioxidant and anti-inflammatory effects on cancer cells. Ellagitannins are bioactive polyphenols present in pomegranate. Pomegranate juice obtained by squeezing the whole fruit has the highest concentration of ellagitannins than any commonly consumed juice and contains the unique ellagitannin, punicalagin. Punicalagin is the known largest molecular weight polyphenol. Pomegranate ellagitannins are not absorbed intact into the blood stream but are hydrolyzed to ellagic acid over several hours in the intestine. Ellagitannins are also metabolized into urolithins by gut flora, which are conjugated in the liver and excreted in the urine. These urolithins are also bioactive and inhibit prostate cancer cell growth...

来源:Hazardous Substances Data Bank (HSDB)

代谢

腹膜内和口服合成的尿石素A导致前列腺组织中摄取尿石素A及其结合物，且前列腺、结肠和肠组织的水平相对于其他器官更高。目前尚不清楚为什么石榴鞣花单宁代谢物在前列腺、结肠和肠组织中的水平相对于研究中其他器官更高。重要的是，生物活性的石榴鞣花单宁代谢物倾向于定位于前列腺组织，结合临床数据表明石榴汁具有抗癌效果，这提示石榴产品可能在前列腺癌化学预防中发挥作用。长期服用石榴汁或石榴提取物后，人前列腺组织中的尿石素是否可以作为生物标志物仍有待确定。

Intraperitoneal and oral administration of synthesized urolithin A led to uptake of urolithin A and its conjugates in prostate tissue, and levels were higher in prostate, colon, and intestinal tissues relative to other organs. It is unclear why pomegranate ellagitannins metabolites localize at higher levels in the prostate, colon, and intestinal tissues relative to the other organs studied. Importantly, the predilection of bioactive pomegranate ellagitannins metabolites to localize in prostate tissue, combined with clinical data demonstrating the anticancer effects of pomegranate juice, suggests the potential for pomegranate products to play a role in prostate cancer chemoprevention. Whether uro-lithins in human prostate tissue can be used as a biomarker following the long-term administration of pomegranate juice or pomegranate extract remains to be determined. /pomegranate extract/

来源:Hazardous Substances Data Bank (HSDB)

代谢

本研究评估了在Sprague-Dawley大鼠中，连续37天口服含有6%石榴醇的饮食可能产生的毒性效应。通过高效液相色谱-二极管阵列检测-串联质谱（HPLC-DAD-MS-MS）在血浆、肝脏和肾脏中鉴定了石榴醇及其相关代谢物。在肝脏和肾脏中检测到了五种与石榴醇相关的代谢物，即两种鞣花酸衍生物、石榴酸、3,8-二羟基-6H-二苯并[b,d]吡喃-6-酮葡萄糖醛酸苷和3,8,10-三羟基-6H-二苯并[b,d]吡喃-6-酮。

... The present study evaluated the possible toxic effect of punicalagin in Sprague-Dawley rats upon repeated oral administration of a 6% punicalagin-containing diet for 37 days. Punicalagin and related metabolites were identified by HPLC-DAD-MS-MS in plasma, liver, and kidney. Five punicalagin-related metabolites were detected in liver and kidney, that is, two ellagic acid derivatives, gallagic acid, 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one glucuronide, and 3,8,10-trihydroxy-6H-dibenzo[b,d]pyran-6-one.

来源:Hazardous Substances Data Bank (HSDB)

代谢

几种果汁据报道会导致食物-药物相互作用，主要是影响细胞色素P450活性；然而，对于果汁对结合反应的影响知之甚少。在测试的几种果汁（苹果、桃子、橙子、菠萝、葡萄柚和石榴）中，石榴汁在Caco-2细胞中强烈抑制了1-萘酚的硫酸结合。这种抑制作用与剂量和培养时间有关，半抑制浓度（IC50）值为2.7%（体积比）。相比之下，所检测的任何果汁在Caco-2细胞中对1-萘酚的葡萄糖醛酸化没有明显的抑制作用。石榴汁中最丰富的抗氧化多酚安石榴苷也被发现能强烈抑制Caco-2细胞中的硫酸结合，IC50为45微摩尔，与石榴汁的一致。这些数据表明，安石榴苷是石榴汁抑制硫酸结合的主要责任物质。作者还证明，石榴汁和安石榴苷都能在体外以与Caco-2细胞中使用的浓度几乎相等的浓度抑制Caco-2细胞中的酚磺基转移酶活性。然而，石榴汁对Caco-2细胞中的磺基转移酶SULT1A家族基因（SULT1A1和SULT1A3）的表达没有影响。这些结果表明，安石榴苷在Caco-2细胞中抑制磺基转移酶活性是1-萘基硫酸积累减少的原因。数据还表明，石榴汁中的成分，很可能是安石榴苷，损害了硫酸结合的肠道功能，这可能会影响药物和食物以及环境中存在的其他化合物的生物利用度。这些效果可能与石榴汁的抗致癌性质有关。

Several fruit juices have been reported to cause food-drug interactions, mainly affecting cytochrome P450 activity; however, little is known about the effects of fruit juices on conjugation reactions. Among several fruit juices tested (apple, peach, orange, pineapple, grapefruit, and pomegranate), pomegranate juice potently inhibited the sulfoconjugation of 1-naphthol in Caco-2 cells. This inhibition was both dose- and culture time-dependent, with a 50% inhibitory concentration (IC(50)) value calculated at 2.7% (vol/vol). In contrast, no obvious inhibition of glucuronidation of 1-naphthol in Caco-2 cells was observed by any of the juices examined. Punicalagin, the most abundant antioxidant polyphenol in pomegranate juice, was also found to strongly inhibit sulfoconjugation in Caco-2 cells with an IC(50) of 45 uM, which is consistent with that of pomegranate juice. These data suggest that punicalagin is mainly responsible for the inhibition of sulfoconjugation by pomegranate juice. /The authors/ additionally demonstrated that pomegranate juice and punicalagin both inhibit phenol sulfotransferase activity in Caco-2 cells in vitro, at concentrations that are almost equivalent to those used in the Caco-2 cells. Pomegranate juice, however, shows no effects on the expression of the sulfotransferase SULT1A family of genes (SULT1A1 and SULT1A3) in Caco-2 cells. These results indicate that the inhibition of sulfotransferase activity by punicalagin in Caco-2 cells is responsible for the reductions seen in 1-naphthyl sulfate accumulation. /The/ data also suggest that constituents of pomegranate juice, most probably punicalagin, impair the enteric functions of sulfoconjugation and that this might have effects upon the bioavailability of drugs and other compounds present in food and in the environment. These effects might be related to the anticarcinogenic properties of pomegranate juice.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

为了寻找含有能够抑制黑色素生物合成的多酚类化合物的植物提取物，我们确定了一种新型的西伯利亚落叶松（Larix sibirica）提取物与石榴果（Punica granatum）提取物的组合，这种组合在Melan-a细胞中显示出协同减少黑色素生物合成的作用。西伯利亚落叶松提取物标准化至含80%的黄杉素，石榴果提取物含有20%的石榴酸，这两种提取物的组合（1:1）与单独使用西伯利亚落叶松或石榴提取物相比，使黑色素含量减少了2倍，而且对细胞活力没有相应的影响。西伯利亚落叶松和石榴果提取物抑制了黑色素的特定基因表达，包括酪氨酸酶（Tyr）、小眼转录因子（Mitf）以及黑色素体结构蛋白（Pmel17和Mart1），但并未抑制酪氨酸酶的酶活性。这些结果表明，西伯利亚落叶松和石榴提取物单独使用或组合使用抑制黑色素生物合成的机制，是通过下调黑色素细胞特定基因的表达，而不是由于抑制酪氨酸酶的酶活性。

In an effort to find botanicals containing polyphenolic compounds with the capacity to inhibit melanin biosynthesis, we identified a novel combination of Siberian larch (Larix sibirica) extract, standardized to 80% taxifolin, and pomegranate fruit (Punica granatum) extract, containing 20% punicalagins, that demonstrates a synergistic reduction of melanin biosynthesis in Melan-a cells. The combination of Siberian larch and pomegranate extracts (1:1) produced a 2-fold reduction in melanin content compared to Siberian larch or pomegranate extracts alone with no corresponding effect on cell viability. Siberian larch and pomegranate fruit extracts inhibited expression of melanocyte specific genes, tyrosinase (Tyr), microphthalmia transcription factor (Mitf), and melanosome structural proteins (Pmel17 and Mart1) but did not inhibit tyrosinase enzyme activity. These results suggest that the mechanism of inhibition of melanin biosynthesis by Siberian larch and pomegranate extracts, alone and in combination, is through downregulation of melanocyte specific genes and not due to inhibition of tyrosinase enzyme activity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

Terminalia catappa L. 是台湾民间广泛用于预防肝癌和治疗肝炎的一种草药。在本文中，作者们研究了T. catappa叶水提取物（TCE）及其主要鞣质成分punicalagin对培养的中国仓鼠卵巢细胞中白消安诱导的遗传毒性的保护作用。用TCE或punicalagin预处理可以防止白消安诱导的hgprt基因突变和DNA链断裂。TCE和punicalagin抑制了白消安诱导的细胞内自由基的产生，这些自由基被识别为超氧阴离子和过氧化氢。TCE和punicalagin对白消安诱导的遗传毒性的有效性至少部分归因于它们的抗氧化潜力。

Terminalia catappa L. is a popular folk medicine for preventing hepatoma and treating hepatitis in Taiwan. In this paper, /the authors/ examined the protective effects of T. catappa leaf water extract (TCE) and its major tannin component, punicalagin, on bleomycin-induced genotoxicity in cultured Chinese hamster ovary cells. Pre-treatment with TCE or punicalagin prevented bleomycin-induced hgprt gene mutations and DNA strand breaks. TCE and punicalagin suppressed the generation of bleomycin-induced intracellular free radicals, identified as superoxides and hydrogen peroxides. The effectiveness of TCE and punicalagin against bleomycin-induced genotoxicity could be, at least in part, due to their antioxidative potentials.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

作者们研究了石榴酸（PC）对体外和体内苯并[a]芘（BP）诱导的DNA加合物的影响。在大鼠肝脏微粒体、适当的共因子和DNA存在的情况下，用载体或石榴酸（1-40微摩尔）孵化BP（1微摩尔）显示出对产生的DNA加合物的剂量依赖性抑制作用，在40微摩尔时几乎完全（97%）抑制。然而，当在体外非微粒体系统中测试时，PC未能抑制抗-BPDE诱导的DNA加合物，这表明微粒体BP-DNA加合物的抑制作用是由于PC抑制了P450 1A1。为了确定其在体内的疗效，雌性S/D大鼠通过饮食（1500 ppm；大约19毫克/天/动物）或皮下聚合物植入物（两个2厘米，200毫克含20%药物负荷；每个植入物40毫克PC）给予石榴酸，然后用皮下聚合物植入物（2厘米，200毫克含10%负荷；20毫克BP/植入物）连续低剂量给予BP，并在10天后处死。通过(32)P后标记分析肺DNA显示，通过植入物给药的PC显著（60%；p=0.029）抑制了DNA加合物；饮食途径显示了温和（34%）但无统计学意义上的抑制作用。此外，通过植入物给药的总PC量比饮食途径大约低38倍。分析肺微粒体显示，细胞色素P450 1A1活性显著抑制，谷胱甘肽诱导增加。发现从植入物中释放的PC是双相的，先是爆发释放，然后逐渐下降。超高效液相色谱分析显示血浆中检测不到PC，但其水解产物，鞣花酸很容易检测到。与饮食组（4.36 +/- 0.83纳克/毫升）相比，植入物组的鞣花酸血浆浓度高出两个数量级（589 +/- 78纳克/毫升）。总的来说，我们的数据显示，通过植入物给药的PC可以大幅降低其有效剂量，并且体内DNA加合物的抑制作用可能是由于PC转化为鞣花酸。

/The authors/ investigated the effect of punicalagin (PC) on benzo[a]pyrene (BP)-induced DNA adducts in vitro and in vivo. Incubation of BP (1 uM) with rat liver microsomes, appropriate co-factors and DNA in the presence of vehicle or punicalagin (1-40 uM) showed dose-dependent inhibition of the resultant DNA adducts, with essentially complete (97%) inhibition at 40 uM. However, PC failed to inhibit anti-BPDE-induced DNA adducts when tested in an in vitro non-microsomal system, suggesting that the inhibition of the microsomal BP-DNA adducts occurred due to inhibition of P450 1A1 by PC. To determine its efficacy in vivo, female S/D rats were administered punicalagin via the diet (1500 ppm; approximately 19 mg/day/animal) or subcutaneous polymeric implants (two 2-cm, 200mg with 20% drug load; 40 mg PC/implant) and then treated with continuous low-dose of BP by a subcutaneous polymeric implant (2 cm, 200mg with 10% load; 20mg BP/implant) and euthanized after 10 days. Analysis of the lung DNA by (32)P-postlabeling showed significant (60%; p=0.029) inhibition of DNA adducts by PC administered via the implants; the dietary route showed modest (34%) but statistically insignificant inhibition. Furthermore, total PC administered by implants was approximately 38-fold lower compared with the dietary route. Analysis of the lung microsomes showed significant inhibition of cytochrome P450 1A1 activity and induction of glutathione. Release of PC from the implants was found to be biphasic starting with a burst release, followed by a gradual decline. Ultra performance liquid chromatography analysis showed no detectable PC in the plasma but its hydrolyzed product, ellagic acid was readily detected. The plasma concentration of ellagic acid was over two orders of magnitude higher (589 +/-78 ng/mL) in the implant group compared with diet (4.36 +/- 0.83 ng/mL). Together, our data show that delivery of PC by implants can reduce its effective dose substantially, and that the inhibition of DNA adducts in vivo occurred presumably due to the conversion of PC to ellagic acid

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

石榴鞣花酸和石榴鞣素是从榄仁树叶中分离出来的，用于治疗皮炎和肝炎。这两种化合物都具有很强的抗氧化活性。评估了石榴鞣花酸和石榴鞣素对大鼠肝脏因四氯化碳（CCl4）诱导的毒性的抗肝毒性活性。血清谷氨酸-草酸转氨酶和谷氨酸-丙酮酸转氨酶的水平因CCl4的给药而增加，而通过药物治疗得以降低。CCl4诱导的肝脏中央静脉周围的病理变化和氧化损伤也从药物治疗中受益。结果显示，石榴鞣花酸和石榴鞣素都具有抗肝毒性活性，但是较大剂量的石榴鞣素会引起肝脏损伤。因此，即使鞣酸在非常小的剂量下具有强烈的抗氧化活性，使用较大剂量的治疗会导致细胞损伤。

Punicalagin and punicalin, isolated from the leaves of Terminalia catappa L., are used to treat dermatitis and hepatitis. Both compounds have strong antioxidative activity. The antihepatotoxic activity of punicalagin and punicalin on carbon tetrachloride (CCl4)-induced toxicity in the rat liver was evaluated. Levels of serum glutamate-oxalate-transaminase and glutamate-pyruvate-trans-aminase were increased by administration of CCl4 and reduced by drug treatment. Histological changes around the liver central vein and oxidation damage induced by CCl4 also benefited from drug treatment. The results show that both punicalagin and punicalin have anti-hepatotoxic activity but that the larger dose of punicalin induced liver damage. Thus even if tannins have strong antioxidant activity at very small doses, treatment with a larger dose will induce cell damage.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者向前倾或将其置于左侧（如果可能的话，头部向下），以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

本研究评估了在Sprague-Dawley大鼠中，连续37天口服含有6%石榴醇的饮食可能产生的毒性效应。通过高效液相色谱-二极管阵列检测-串联质谱（HPLC-DAD-MS-MS）在血浆、肝脏和肾脏中鉴定了石榴醇及其相关代谢物。在肝脏和肾脏中检测到五种与石榴醇相关的代谢物，即两种鞣花酸衍生物、石榴酸、3,8-二羟基-6H-二苯并[b,d]吡喃-6-酮葡萄糖醛酸苷和3,8,10-三羟基-6H-二苯并[b,d]吡喃-6-酮。

... The present study evaluated the possible toxic effect of punicalagin in Sprague-Dawley rats upon repeated oral administration of a 6% punicalagin-containing diet for 37 days. Punicalagin and related metabolites were identified by HPLC-DAD-MS-MS in plasma, liver, and kidney. Five punicalagin-related metabolites were detected in liver and kidney, that is, two ellagic acid derivatives, gallagic acid, 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one glucuronide, and 3,8,10-trihydroxy-6H-dibenzo[b,d]pyran-6-one.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  α-punicalagin 以 甲醇 为溶剂， 生成 β-punicalagin
  参考文献：
  名称：

  Doig, Andrew J.; Williams, Dudley H.; Oelrichs, Peter B., Journal of the Chemical Society. Perkin transactions I, 1990, # 8, p. 2317 - 2321

  摘要：

  DOI：
• 作为产物：
  描述：

  β-punicalagin 以 甲醇 为溶剂， 生成 α-punicalagin
  参考文献：
  名称：

  Doig, Andrew J.; Williams, Dudley H.; Oelrichs, Peter B., Journal of the Chemical Society. Perkin transactions I, 1990, # 8, p. 2317 - 2321

  摘要：

  DOI：

文献信息

• DOIG, ANDREW J.;WILLIAMS, DUDLEY H.;OELRICHS, PETER B.;BACZYNSKY, LUBOMIR, J. CHEM. SOC. PERKIN TRANS. PT 1,(1990) N, C. 2317-2321
  作者：DOIG, ANDREW J.、WILLIAMS, DUDLEY H.、OELRICHS, PETER B.、BACZYNSKY, LUBOMIR

  DOI：——

  日期：——
• Doig, Andrew J.; Williams, Dudley H.; Oelrichs, Peter B., Journal of the Chemical Society. Perkin transactions I, <hi>1990</hi>, # 8, p. 2317 - 2321
  作者：Doig, Andrew J.、Williams, Dudley H.、Oelrichs, Peter B.、Baczynskyj, Lubomir

  DOI：——

  日期：——