DL-α-生育酚 | 10191-41-0

• 物质功能分类: 食品添加剂 - 抗氧化剂
• 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
• 中文名称: DL-α-生育酚
• 中文别名: 维生素E；维它命E油；DL-alpha-生育酚；3,4-二氢-2,5,7,8-四甲基-2-(4,8,12-三甲基十三烷基)-6-色满醇
• 英文名称: vitamin E
• 英文别名: DLα-tocopherol；α-tocopherol；tocopherol；alpha-tocopherol；(all-rac)-α-tocopherol；2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-ol；all racemic-α-tocopherol；±-α-tocopherol；DL-a-tocopherol；DL-alpha-Tocopherol；2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydrochromen-6-ol
• CAS: 10191-41-0；1406-18-4
• 化学式: C₂₉H₅₀O₂
• mdl: MFCD00006848
• 分子量: 430.715
• InChiKey: GVJHHUAWPYXKBD-UHFFFAOYSA-N

物化性质

• 熔点：
  2-4°C
• 比旋光度：
  [α]D20 - 0.02 - +0.02゜ (neat)
• 沸点：
  200-220°C 0,1mm
• 密度：
  0.950 g/mL at 20 °C(lit.)
• 闪点：
  240°C
• 溶解度：
  H2O：不溶
• LogP：
  12.2 at 25℃
• 物理描述：
  Liquid
• 颜色/状态：
  Slightly viscous, pale yellow oil
• 蒸汽压力：
  1.4X10-8 mm Hg at 25 °C (est)
• 稳定性/保质期：

  耐热性较好，但遇光后可能会发生氧化，导致色泽变深。

• 旋光度：
  [α]D/25 0° ± 0,05° (1 in 10 solution in chloroform)
• 折光率：
  Index of refraction: 1.5045 at 25 °C/D
• 解离常数：
  pKa = 10.8 (hydroxy) (est)
• 碰撞截面：
  219.7 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]
• 保留指数：
  3149.5;3149.4;3138;3142;3112;3130

计算性质

• 辛醇/水分配系数(LogP)：
  10.7
• 重原子数：
  31
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  29.5
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

过量的生育酚会转化为它们相应的羧乙基羟基色原（CEHC），这取决于生育酚的异构体。更深入地讲，生育酚的代谢始于肝脏代谢，这是由CYP4F2/CYP3A4依赖的ω-羟基化作用领导的，这种作用导致13'-羧基色醇的形成。代谢途径随后经过五个周期的β-氧化。β-氧化周期通过缩短侧链发挥作用，第一个周期导致羧基二甲基癸基羟基色醇的形成，接着是羧基甲基辛基羟基色醇。这两种代谢物被归类为长链代谢物，它们不会通过尿液排出。两轮β-氧化产生的中间链代谢物包括羧基甲基己基羟基色醇和羧基甲基丁基羟基色醇。这些中间链代谢物可以在人类的粪便和尿液中找到。如前所述，生育酚的分解终端产物是CEHC，它主要可以在尿液和粪便中找到。在人类和小鼠的粪便中已经检测到两种新的代谢物。这些新的代谢物是12'-羟基色醇和11'-羟基色醇。由于它们的化学性质，人们认为这些代谢物可以作为ω-1和ω-2羟基化的证据，这导致12'-OH的氧化受损，随后是侧链的截断。

Excess tocopherol is converted into their corresponding carboxyethylhydroxychroman (CEHC), based on the isomer of tocopherol. More deeply, the metabolism of tocopherol begins with the hepatic metabolism which is led by a CYP4F2/CYP3A4-dependent ω-hydroxylation of the side chains which leads to the formation of 13'-carboxychromanol. The metabolic pathway is followed by five cycles of β-oxidation. The β-oxidation cycles function by shortening the side chains, the first cycle results in the formation of carboxydimethyldecylhydroxychromanol followed by carboxymethyloctylhydroxychromanol. These two metabolites are categorized as long-chain metabolites and they are not excreted in the urine. Some intermediate-chain metabolites that are products of two rounds of β-oxidation are carboxymethylhexylhydroxychromanol and carboxymethylbutylhydroxychromanol. These intermediate-chain metabolites can be found in human feces and urine. The catabolic end-product of tocopherols, as stated before, is CEHC which can be largely found in urine and feces. Two new metabolites have been detected in human and mice feces. These new metabolites are 12'-hydroxychromanol and 11'-hydroxychromanol. Because of their chemistry, it is thought that these metabolites can be the evidence for a ω-1 and ω-2 hydroxylation which leads to an impaired oxidation of 12'-OH followed side-chain truncation.

来源:DrugBank

毒理性

• 毒性总结

识别和使用：dl-α-生育酚是一种轻微粘稠、淡黄色的油。这是一种合成形式的α-生育酚。天然α-生育酚的活性，按等重量计算，至少是合成形式的两倍。dl-α-生育酚被用作脂肪和油以及动物饲料中的抗氧化剂。它也被用作实验性药物和膳食补充剂。人类暴露和毒性：在23,908名接受贴片测试的患者中，有219人（0.9%）将防晒霜编码为过敏原来源。防晒霜中最常见的三种过敏原是苯甲酮-3、dl-α-生育酚和香料混合物。中等剂量的合成dl-α-生育酚醋酸酯作为膳食补充剂，并未显著延长健康志愿者的出血或血小板聚集时间。根据几份报告，dl-α-生育酚在健康志愿者中提供了对抗运动诱导的氧化损伤的保护。体外实验表明，dl-α-生育酚普遍抑制细胞增殖，其中乳腺癌和前列腺癌细胞对红细胞白血病细胞明显更敏感。动物研究：在接触dl-α-生育酚醋酸酯3-8周的小鸡中，它导致了凝血酶原时间的延长、网织红细胞增多和血红蛋白浓度的降低。补充dl-α-生育酚增加了牛体内的α-生育酚浓度；然而，对繁殖效率的影响很小。向白细胞培养物中添加dl-α-生育酚减少了由7,12-二甲基苯并(a)蒽引起的染色体断裂的数量。dl-α-生育酚显著减少了malonaldehyde和β-丙烯内酯在五种 Salmonella typhimurium 菌株中的致突变效应，这些菌株通过移码机制发生突变。

IDENTIFICATION AND USE: dl-alpha-Tocopherol is a slightly viscous, pale yellow oil. This is a synthetic form of alpha tocopherol. The activity of natural alpha-tocopherol on an equal weight basis, is at least twice as high as the synthetic form. dl-alpha-Tocopherol is used as an antioxidant in fats and oils and in animal feed. It is also used as experimental medication and as a dietary supplement. HUMAN EXPOSURE AND TOXICITY: Of 23,908 patients patch tested, 219 (0.9%) had sunscreen coded as an allergen source. The top 3 most frequent allergens in sunscreens were benzophenone-3, dl-alpha-tocopherol, and fragrance mix. Dietary supplementation with moderate dosage synthetic dl-alpha-tocopherol acetate did not significantly prolong bleeding or platelet aggregation in healthy volunteers. dl-alpha-Tocopherol provided protection against exercise-induced oxidative injury in healthy volunteers according to several reports. In vitro experiments demonstrated general inhibition of cell proliferation by dl-alpha-tocopherol, with breast and prostate cancer cells distinctly more sensitive than erythroleukemia cells. ANIMAL STUDIES: In chicks exposed to dl-alpha-tocopherol acetate for 3-8 weeks it caused prolonged prothrombin times, reticulocytosis, and a reduced hematocrit value. Supplementation of dl-alpha-tocopherol increased alpha-tocopherol concentration in cows; however, effects on reproductive efficiency were minimal. The addition of dl-alpha-tocopherol to leucocyte cultures reduced the number of chromosome breaks induced by 7,12-dimethylbenz(a)anthracene. dl-alpha-Tocopherol markedly reduced the mutagenic effect of malonaldehyde and beta-propiolactone in five strains of Salmonella typhimurium, which mutated with a frameshift mechanism.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概要：维生素E是人类乳汁的正常组成部分。母亲肥胖、吸烟以及可能的早产（妊娠年龄小于37周）与乳汁中维生素E水平较低有关。哺乳期母亲可能需要补充维生素E，以达到推荐的每日允许量19毫克。从产前多种维生素中每日补充维生素E可以安全地适度提高乳汁中维生素E水平，并与不补充相比，改善母乳喂养婴儿的维生素E状况。更高每日剂量的研究尚未进行。摄入多不饱和脂肪酸较高的女性乳汁中α-生育酚含量较高。 ◉ 巴氏杀菌法（62.5°C，30分钟）不会降低乳汁的抗氧化能力，这是维生素E水平的反映。 ◉ 对母乳喂养婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和乳汁的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Vitamin E is a normal component of human milk. Maternal obesity, smoking and possibly preterm birth (<37 weeks gestational age) are associated with lower milk vitamin E levels. Lactating mothers may need to supplement their dietary intake of vitamin E to achieve the recommended daily allowance of 19 mg. Daily maternal vitamin E supplementation from prenatal multivitamins can safely and modestly increase milk vitamin E levels and improve the vitamin E status of the breastfed infant compared to no supplementation. Higher daily dosages have not been studied. Women with higher intakes of polyunsaturated fatty acids have higher alpha-tocopherol in breastmilk. Holder pasteurization (62.5 degrees C for 30 minutes) does not reduce milk antioxidant capacity, which is a reflection of vitamin E levels. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

炎症性肠病通常与缺铁性贫血有关，可能需要口服铁补充剂。然而，铁可能通过Fenton反应增加氧化应激，从而加剧疾病。本研究旨在确定口服铁补充剂是否会增加硫酸右旋糖酐钠（DSS）诱导的结肠炎大鼠的肠炎症和氧化应激，以及添加抗氧化剂维生素E是否能减少这种有害影响。研究了四组大鼠，它们在饮水中摄入50 g/L DSS，持续7天，并分别喂食：对照组，非纯化饮食（铁，270 mg/kg，dl-α-生育酚醋酸酯，49 mg/kg）；饮食+铁（铁，3000 mg/kg）；饮食+维生素E（dl-α-生育酚醋酸酯，2000 mg/kg）以及饮食+铁和维生素E，每种浓度与上述相同。测量体重变化、直肠出血、组织学评分、血浆和结肠脂质过氧化物（LPO）、血浆8-异前列腺素、结肠谷胱甘肽过氧化物酶（GPx）和血浆维生素E。铁补充剂增加了疾病活动，表现为组织学评分更高和直肠出血更重。这与结肠和血浆LPO以及血浆8-异前列腺素的增加以及结肠GPx的减少有关。维生素E补充剂减少了结肠炎症和直肠出血，但并未影响氧化应激，这表明减少炎症的另一种机制。总之，在这个结肠炎模型中，口服铁补充剂导致了疾病活动的增加。维生素E减少了这种对疾病活动的不利影响。因此，将维生素E添加到口服铁补充剂中可能有益。

Inflammatory bowel disease is often associated with iron deficiency anemia and oral iron supplementation may be required. However, iron may increase oxidative stress through the Fenton reaction and thus exacerbate the disease. This study was designed to determine in rats with dextran sulfate sodium (DSS)-induced colitis whether oral iron supplementation increases intestinal inflammation and oxidative stress and whether the addition of an antioxidant, vitamin E, would reduce this detrimental effect. Four groups of rats that consumed 50 g/L DSS in drinking water were studied for 7 d and were fed: a control, nonpurified diet (iron, 270 mg, and dl-alpha-tocopherol acetate, 49 mg/kg); diet + iron (iron, 3000 mg/kg); diet + vitamin E (dl-alpha-tocopherol acetate, 2000 mg/kg) and the diet + both iron and vitamin E, each at the same concentrations as above. Body weight change, rectal bleeding, histological scores, plasma and colonic lipid peroxides (LPO), plasma 8-isoprostane, colonic glutathione peroxidase (GPx) and plasma vitamin E were measured. Iron supplementation increased disease activity as demonstrated by higher histological scores and heavier rectal bleeding. This was associated with an increase in colonic and plasma LPO and plasma 8-isoprostane as well as a decrease in colonic GPx. Vitamin E supplementation decreased colonic inflammation and rectal bleeding but did not affect oxidative stress, suggesting another mechanism for reducing inflammation. In conclusion, oral iron supplementation resulted in an increase in disease activity in this model of colitis. This detrimental effect on disease activity was reduced by vitamin E. Therefore, the addition of vitamin E to oral iron supplementation may be beneficial.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

先前的研究表明，β-胡萝卜素和α-生育酚可以协同作用，抑制实验性诱导的口腔癌的生长。关于抗氧化剂的协同抗癌活性的初步研究已经扩展到包括还原型谷胱甘肽和抗坏血酸（维生素C）。六十只雄性仓鼠（4-5周龄）被平均分成六组。第1-6组用7,12-二甲基苯并[a]蒽（DMBA）（0.5%溶液）处理。第2组接受一种混合物，其中包含等量的β-胡萝卜素、dl-α-生育酚（维生素E）、谷胱甘肽和L-抗坏血酸（维生素C）（12.5微克），通过移液管口服给药。第3-6组分别单独用β-胡萝卜素（50微克）、维生素E（50微克）、单独谷胱甘肽（50微克）和单独维生素（50微克）处理。在12周和14周时对动物实施安乐死。计数并测量肿瘤，并计算每个实验组的肿瘤负荷。抗氧化剂混合物显著减少了肿瘤负荷，而β-胡萝卜素、维生素E和还原型谷胱甘肽治疗也减少了肿瘤负荷。β-胡萝卜素和谷胱甘肽作为单一试剂的化学预防作用大于维生素E。相比之下，维生素C治疗没有产生抗肿瘤效果，但在第14周增加了肿瘤负荷。这种抗氧化剂混合物产生了显著的协同化学预防口腔癌的效果。

Previous studies have shown that beta-carotene and alpha-tocopherol can act synergistically to inhibit the growth of experimentally induced oral cancer. The initial studies on the synergistic anticancer activity of antioxidants have been extended to include reduced glutathione and ascorbic acid. Sixty male hamsters (4-5 wks old) were divided into six equal groups. Groups 1-6 were treated with 7,12-dimethylbenz[a]anthracene (DMBA) (0.5% solution). Group 2 received a mixture containing equal amounts of beta-carotene, dl-alpha-tocopherol (vitamin E), glutathione, and l-ascorbic acid (vitamin C) (12.5 micrograms) delivered orally by pipette. Groups 3-6 were treated with beta-carotene alone (50 micrograms), vitamin E alone (50 micrograms), glutathione (50 micrograms) alone, and vitamin C alone (50 micrograms). Animals were euthanized at 12 and 14 weeks. Tumors were counted and measured, and tumor burden was calculated for each experimental group. The mixture of antioxidants significantly reduced tumor burden, whereas the beta-carotene, vitamin E, and reduced glutathione treatments also reduced tumor burden. beta-Carotene and glutathione provided greater levels of chemoprevention than vitamin E as single agents. In contrast, vitamin C treatment produced no antitumor effect but increased tumor burden by Week 14. This mixture of antioxidants produced a significant synergistic chemoprevention of oral cancer.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

硝酸三铁(Fe-NTA)是一种强效的肾毒性剂。在这篇通讯中，我们展示了DL-α-生育酚(维生素E)对硝酸三铁(Fe-NTA)诱导的大鼠肾氧化应激、毒性和过度增殖反应的调节作用。Fe-NTA处理增加了肾微粒体膜对铁-抗坏血酸诱导的脂质过氧化和过氧化氢生成的敏感性，这伴随着肾抗氧化酶活性下降，包括过氧化氢酶、谷胱甘肽过氧化物酶、谷胱甘肽还原酶和谷胱甘肽-S-转移酶，以及肾谷胱甘肽水平的耗竭。与此平行，血尿素氮和血清肌酐急剧增加。此外，Fe-NTA处理还增强了肾鸟氨酸脱羧酶活性(ODC)并增加了[(3)H]胸腺嘧啶核苷酸在肾DNA中的掺入。在Fe-NTA给药前1周，每天用维生素E预处理动物，可减少Fe-NTA介导的损伤。铁-抗坏血酸诱导的肾微粒体膜脂质过氧化敏感性增强和过氧化氢生成显著降低(P < 0.05)。此外，耗竭的谷胱甘肽水平和抑制的抗氧化酶活性显著恢复到正常水平(P < 0.05)。类似地，表示肾损伤的血尿素氮和血清肌酐水平在较高剂量的维生素E下降低了约50%。维生素E预处理显著降低了Fe-NTA介导的ODC活性的增加和DNA中[(3)H]胸腺嘧啶核苷酸掺入的增加。维生素E的保护效果呈剂量依赖性。总之，我们的数据表明，维生素E在肾脏中是一种有效的化学预防剂，可能抑制Fe-NTA诱导的肾毒性。

Ferric nitrilotriacetate (Fe-NTA) is a potent nephrotoxic agent. In this communication, we show the modulatory effect of DL-alpha-tocopherol (Vitamin-E) on ferric nitrilotriacetate (Fe-NTA)-induced renal oxidative stress, toxicity and hyperproliferative response in rats. Fe-NTA-treatment enhances the susceptibility of renal microsomal membrane for iron-ascorbate-induced lipid peroxidation and hydrogen peroxide generation which are accompanied by a decrease in the activities of renal antioxidant enzymes, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase and depletion in the level of renal glutathione. Parallel to these changes, a sharp increase in blood urea nitrogen and serum creatinine has been observed. In addition, Fe-NTA-treatment also enhances renal ornithine decarboxylase activity (ODC) and increases [(3)H]thymidine incorporation in renal DNA. Prophylactic treatment of animals with /vitamin E/ Vit.E daily for 1 week prior to the administration of Fe-NTA resulted in the diminution of Fe-NTA-mediated damage. Enhanced susceptibility of renal microsomal membrane for lipid peroxidation induced by iron-ascorbate and hydrogen peroxide generation were significantly reduced (P < 0.05). In addition, the depleted level of glutathione and inhibited activities of antioxidant enzymes recovered to significant levels (P < 0.05). Similarly, the enhanced blood urea nitrogen and serum creatinine levels which are indicative of renal injury showed a reduction of about 50% at a higher dose of Vit.E. The pretreatment of rats with Vit.E reduced the Fe-NTA-mediated induction in ODC activity and enhancement in [(3)H]thymidine incorporation in DNA. The protective effect of Vit.E was dose dependent. In summary, our data suggest that Vit.E is an effective chemopreventive agent in kidney and may suppress Fe-NTA-induced renal toxicity.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

在消化道的维生素E（生育酚）吸收需要脂肪的存在。生育酚的生物利用率高度依赖于所给予的同分异构体的类型，其中α-生育酚的生物利用率可达36%。这种同分异构体的特异性也决定了肠道的渗透性，其中γ-生育酚的渗透性非常低。口服给药后，δ-生育酚的Cmax（最大血药浓度）为1353.79纳克/毫升，γ-生育酚为547.45纳克/毫升，β-生育酚为704.16纳克/毫升，α-生育酚为2754.36纳克/毫升。δ-生育酚、γ-生育酚和β-生育酚的Tmax（达到最大血药浓度的时间）为三到四小时，而α-生育酚的Tmax约为六小时。

The absorption of tocopherol in the digestive tract requires the presence of fat. The bioavailability of tocopherols is highly dependent on the type of isomer that is administered where the alpha-tocopherol can present a bioavailability of 36%. This isomer specificity also determines the intestinal permeability in which the gamma-tocopherol presents a very low permeability. After oral administration, the Cmax was 1353.79 ng/ml for δ-tocopherol, 547.45 ng/ml for γ-tocopherol, 704.16 ng/ml for β-tocopherol, and 2754.36 ng/ml for α-tocopherol. The Tmax is three to four hours for δ-tocopherol, γ-tocopherol, and β-tocopherol and about six hours for α-tocopherol.

来源:DrugBank

吸收、分配和排泄

• 消除途径

维生素E的药代动力学资料显示，与生育三烯酚相比，生育酚的排泄时间更长。不同的结合代谢物根据侧链长度的不同，通过尿液或粪便排出。由于它们的极性，中链和短链代谢物以葡萄糖苷结合物的形式通过尿液排出。粪便中可以找到所有代谢物和前体的混合物。长链代谢物在粪便中的总代谢物中占比超过60%。据估计，粪便排泄甚至占到给药剂量的80%。

The pharmacokinetic profile of tocopherol indicates a longer time of excretion for tocopherols when compared to tocotrienols. The different conjugated metabolites are excreted in the urine or feces depending on the length of their side-chain. Due to their polarity, intermediate-chain metabolites and short-chain metabolites are excreted via urine as glucoside conjugates. A mixture of all the metabolites and precursors can be found in feces. The long-chain metabolites correspond to >60% of the total metabolites in feces. It is estimated that the fecal excretion accounts for even 80% of the administered dose.

来源:DrugBank

吸收、分配和排泄