CN1314943A - 生产具有高含量黄酮类化合物和酚类化合物的植物的方法 - Google Patents
生产具有高含量黄酮类化合物和酚类化合物的植物的方法 Download PDFInfo
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Abstract
在用于增加植物中黄酮类化合物含量的方法中,通过分子遗传学方法生产植物,其中降低了黄烷酮3－羟化酶的活性。
Description
本发明涉及一种通过分子遗传学方法增加植物中黄酮类化合物和酚类成分的含量的方法，因此，该由分子遗传学方法制备的植物具有降低的黄烷酮3-羟化酶的活性。
此外，在本发明的方法中，通过分子生物学方法(例如反义构建、共抑制、表达特异性抗体或表达特异性抑制剂)在完整植物或植物部位中完全或部分、永久或短暂地降低了黄烷酮3-羟化酶的活性。
本发明另外涉及具有高含量黄酮类化合物和酚类成分的植物，其黄烷酮3-羟化酶的酶活性得到了降低。
此外，本发明涉及通过本发明方法生产的植物或这些植物的部位用作食品、添加剂或用于生产人和动物的治疗用组合物、保健用组合物或补药(汁、茶、提取物、发酵产品)和生产化妆品的用途。
在植物中发现了大量酚类物质，例如咖啡酸、阿魏酸、绿原酸、没食子酸、丁子香酚、木素、香豆素类、木质素类、芪类(虎杖苷(polydatin)、白藜芦醇)、黄酮类化合物(黄酮类、儿茶精类、黄烷酮类、花色素类、异黄酮类)和聚甲氧基化黄酮类。因此，一般酚类也是大量植物衍生的食品和刺激剂的组成成分。某些酚类物质具有特别重要意义，因为在与食物一起吸收后，它们可以在人或动物代谢过程中发挥抗氧化剂作用(Baum,B.O.；Perun,A.L.“抗氧化剂功效与结构”-Soc.Plast.Engrs.Trans.2:250-257,(1962)；Gardner,P.T.；McPhail,D.B.；Duthie,G.G.“在水和有机介质中茶的抗氧化剂潜能的电子自旋共振光谱评估”-J.Sci.FoodAgric.76:257-262(1997)；Rice-Evans,C.A.；Miller,N.J.；Pananga,G.“黄酮类化合物和酚酸类的结构-抗氧化活性的关系”-FreeRaic.Biol.Med.20；933-956,(1996)；Salah,N.；Miller,N.J.；Paganga,G.；Tijburg,L.；Bolwell,G.P.；Rice-Evans,C.“多酚类黄酮化合物作为水相自由基清除剂和作为断链的抗氧化剂”-Arch Biochem Biophys 322:339-346,(1995)；Stryer,L.Biochemistry S.Francisco:Freeman,(1975)；Vieira,O.；Escargueil-Blanc,I.；Meilhac,O.；Basile,J.P.；Laranjinha,J.；Almeida,L.；Salvayre,R.；Negre-Salvayre,A.，“食物酚类化合物对由氧化的LDL诱导的培养的人内皮细胞程序死亡的影响”-Br J Pharmacol 123:565-573,(1998))。此外，多酚类还对细胞代谢具有多重性作用。特别是它们可调制信号转导酶类诸如蛋白激酶C、酪氨酸蛋白激酶和磷脂酰肌醇3-激酶(Agullo,G.；Gamet-payrastre,L.；Manenti,S.；Viala,C.；Remesy,C.；Chap,H.；Payrastre,B.“黄酮类化合物结构与抑制磷脂酰肌醇3-激酶之间的关系：酪氨酸激酶和蛋白激酶C抑制作用的比较”-BiochemPharmacol 53:1649-1657,(1997)；Ferriola,P.C.；Cody,V.；Middleton,E.“由植物黄酮类化合物导致的蛋白激酶C的抑制作用”、“动力学机制与结构活性的关系”-Biochem Pharmacol 38:1617-1624,(1989)；Cushman,M.；Nagarathman,D.；Burg,D.L.；Geahlen,R.L.“黄酮类化合物类似物的合成和蛋白质-酪氨酸激酶抑制活性”-J Meed Chem 34:798-806,(1991)；Hagiwara,M.；Inoue,S.；Tanaka,T.；Nunoki,K.；Ito,M.；Hidaka,H.“作为酪氨酸蛋白激酶类和丝氨酸/苏氨酸蛋白激酶类抑制剂的黄酮化合物的不同作用”-Biochem Pharmacol 37:2987-2992,(1998)),这些酶可以下调诱导型NO合酶(Kobuchi,H.；Droy-Lefaix,M.T.；Christen,Y.；Packer,L.“银杏提取物(EGb761)：在巨噬细胞细胞系RAW264.7中对氧化氮产生的抑制作用”-Biochem Pharmacol53:897-903,(1997)并调节例如白细胞介素(interleucins)和粘附分子(ICAM-1、VCAM-1)的基因表达(Kobuchi,H.；Droy-Lefaix,M.T.；Christen,Y.；Packer,L.“银杏提取物(EGb761)：在巨噬细胞细胞系RAW 264.7中对氧化氮产生的抑制作用”-BiochemPharmacol 53:897-903,(1997)；Wolle,J.；Hill,R.R.；Ferguson,E.；Devall,L.J.；Trivedi,B.K.；Newton,R.S.；Saxena,U.“新型黄酮类化合物对肿瘤坏死因子诱导的血管细胞粘附分子-1基因表达的选择性抑制作用。对转录因子NF-kB没有作用”-Atherioscler Thromb Vasc Biol 16:1501-1508,(1996))。目前可接受的观点是这些作用有利于预防梗死、心血管疾病、糖尿病、各种确定的癌症、肿瘤和其它慢性疾病(Bertuglia,S.；Malandrino,S.；Colantuoni,A.“天然黄酮类化合物翠雀素对糖尿病性微血管病的作用”-Arznei-Forsch/Drug Res 45:481-485,(1995)；Griffiths,K.；Adlercreutz,H.；Boyle,P.；Denis,L.；Nicholson,R.I.；Morton,M.S.Nutrition and Cancer Oxford:Isis Medical Media,(1996)；Hertog,M.G.L.；Fesrens,E.J.M.；Hollman,P.C.K.；Katan,M.B.；Kromhout,D.“食物抗氧化剂黄酮类化合物和冠心病的危害：Zutphen晚期研究”-TheLancet 342:1007-1011,(1993)；Kapiotis,S.；Hermann,M.；Held,I.；Seelos,C.；Ehringer,H.；Gmeiner,B.M.“食物衍生的血管发生抑制剂染料木黄酮预防LDL氧化并防止内皮细胞被致动脉粥样化LDL所损害”-Arterioscler Thromb Vasc Biol 17:2868-74,(1997)；Stampfer,M.J.；Hennekens,C.H.；Manson,J.E.；Colditz,G.A.Rosner,B.；Willet,W.C.“女性中维生素E消耗与冠脉疾病危害”-New Engl J Med 328:1444-1449,(1993)；Tijburg,L.B.M.；Mattern,T.；Folts,J.D.；Weisgerber,U.M.；Katan,M.B.“茶的黄酮类化合物与心血管疾病：综述”-Crit Rev Food Sci Nutr 37:771-785,(1997)；Krik,E.A.；Sutherland,P.；Wang,S.A.；Chait,A.；Leboeuf,R.C.“食物的黄酮类化合物降低C57BL/6小鼠而非LDL受体缺陷小鼠的血浆胆固醇和动脉粥样硬化”-J Nutr 128:954-9,(1998)-参考文献-)。一系列治疗用组合物、保健用组合物和补药的作用以其酚类物质含量为基础，它们由此获自合适的植物(Gerritsen,M.E.；Carley,W.W.；Ranges,G.E.；Shen,C.P.；Phan,S.A.；Ligon,G.F.；Perry,C.A.“黄酮类化合物抑制细胞因子诱导的内皮细胞粘着蛋白的基因表达”-Am J Pathol 147:278-292,(1995)；Lin,J.K.；Chen,Y.C.；Huang,Y.T.；lin-Shiau,S.Y.“抑制蛋白激酶C和核癌基因表达作为芹菜配基和姜黄色素对癌症化学预防作用的可能的分子机理”-J Cell Biochem Suppl 28-29:39-48,1997；Zi,X.；Mukhtar,H.；Agarval,R.“黄酮类化合物抗氧化剂水飞蓟素的新癌症化学预防作用：抑制内源性肿瘤启动子TBFα的mRNA表达”-Biochem Biophys Res Comm 239:334-339,1997)。此外，已知某些植物衍生的食品或由它们制备的刺激剂对各种疾病具有确定的作用。例如，在白葡萄酒而非红葡萄酒中发现的白藜芦醇(还包括其它成分)对梗死、心血管疾病和癌症起作用(Gelm,B.D.；McAndrews,J.M.；Chien,P.-Y；Jameson,J.L.“在葡萄和葡萄酒中发现的多酚类化合物白藜芦醇是雌激素受体的兴奋剂”-Proc Natl Acad Sci USA 94:14138-14143,(1997)；Jang,M.；Cai,L.；Udeani,G.O.；Slowing,K.V.；Thomas,C.F.；Beecher,C.W.W.；Fong,H.H.S.；Farnsworth,N.R.；Kinghorn,A.D.；Mehtha,R.G.；Moon,R.C.,Pezzuto,J.M.“来源于葡萄的天然产物白藜芦醇的癌症化学预防作用”-Science 275:218-220,(1997)。在诸如儿茶素、表儿茶酸-3-没食子酸、表棓儿茶素和表棓儿茶素-3-没食子酸这样的物质中也发现了类似作用，上述物质均是在茶(Camellia sinensis)叶中发现的。特别地，用未发酵的茶叶(绿茶)制成的饮料具有保健作用(Hu,G.；Han,C.；Chen,J.“用绿茶和(-)-表棓儿茶素没食子酸抑制小鼠体内的癌基因的表达”-Nutr Cancer 24:203-209；(1995)；Scholz,E；Bertram,B.Camellia sinensis(L.)O.Kuntze.Der Teestrauch[the teashrub].Z.Phytotherapie 17:235-250,(1995)；Yu,R.；Jiao,J.J.；Duh,J.L.；Gudehithlu,K.；Tan,T.H.；Kong,A.N.“用绿茶的多酚类激活促分裂原激活的蛋白激酶类：调节抗氧化反应性元件介导的Ⅱ期酶基因表达中的潜在信号途径”-Carcinigenesis 18:451-456,(1997)；Jankun,J.；Seiman,S.H.；Swiercz,R.“为什么饮用绿茶可以预防癌症”-Nature 387:561,(1997)。此外，来自桔果的聚甲氧基化黄酮类也表现出潜在的抗癌作用(Chem,J.；Montanari,A.M.；Widmer,W.W.“分离自冷压dancy红桔果皮油固体的两种新型聚甲氧基化(polymethoxylierte)黄酮，它们属于一类具有潜在抗癌活性的化合物”-J Agric Food Chem 45:364-368,(1997))。
本发明的目的是寻找到一种增加农作物植物黄酮类化合物和酚类成分含量的简便而低廉的方法。
我们已经发现：以酰基环己烷二酮类的生长调节剂进行生理研究为出发点，通过目前可获得的基因工程方法可以生产出以高含量治疗、保健或滋补成分为特征的植物，来实现上述目的。
将诸如前环己烷二酮-钙(Prohexadion-Ca)和Trinexapac-ethyl(早先称作：Cimectacarb)这样的酰基环己烷二酮类用作抑制植物纵向生长的生物调节剂。其生物调节作用的原因在于它们可阻断促进纵向生长的赤霉素的生物合成。由于它们与2-酮戊二酸(oxoglutarsure)的结构相关性，所以它们可抑制需要2-酮戊二酸作为共底物的某些双加氧酶类(Rademacher,W，在(PlantBiochemical Regulators)中的“植物生长延缓剂的生化作用”，Gausman,HW(编辑)，Marcel Dekker,Inc.,New York,pp.169-200(1991))。已知这类化合物也参与酚类的代谢且由此能够在各种植物品种中抑制花色素形成(Rademacher,W等，在《(Progress in PlantGrowth Regulation)中的“酰基环己烷二酮类-一类新型生长延缓剂的作用方式”，Kaessen,CM,van loon,LC,Vreugdenhil,D(编辑)，Kluwer Academic Publishers,Dordrecht(1992))。认为这种对酚类成分平衡的作用是前己二酮-钙抗火烧病副作用的原因(Rademacher,W等，“前己二酮-钙-一种用于具有令人感兴趣的生化特征的苹果的新型植物生长调节剂，Poster在1998年7月7-10日在芝加哥举行的第25届美国植物生长调节协会年会上提出”)。A.Lux-Endrich(1998年在Weihenstephan的慕尼黑科技大学的PhD论文)发现：在她对前己二酮-钙抗火烧病作用机理的研究过程中，在苹果细胞培养物中，前己二酮-钙引起了酚类物质含量增加了几倍以上，在此过程中，发现了一系列通常没有找到的酚类。在这些研究中还发现前己二酮-钙可使苹果苗组织中出现相对高含量的Luteoliflavan和北美圣草素。Luteoliflavan通常不会出现在苹果组织中，而北美圣草素仅作为黄酮类化合物代谢的中间产物以小量出现。然而，在经处理的组织中没有检测到预计的黄酮类化合物儿茶素和花青素或它们仅以明显减少的量出现(S.Rmmelt等在第8届国际火烧病研讨会上提交的论文，Kusadasi,Turkey,1998年10月12-15日)。
目前可接受的观点是前环己烷二酮-钙、trinexapac-ethyl和其它酰基环己烷二酮类可抑制在酚类物质代谢中起重要作用的2-酮戊二酸-依赖性羟化酶类。它们主要是查耳酮合成酶(CHS)和黄烷酮3-羟化酶(F3H)(W.Heller和G.Forkman，在(Flavonoids)中的“生物合成”，Harborne,JB(编辑)，Chapman和Hall,New York,1988)。然而，不能排除酰基环己烷二酮类还可抑制其它目前还未知的其它2-酮戊二酸-依赖性羟化酶类。另外，很明显，还注意到植物中缺乏儿茶素、花青素和其它黄酮类化合物合成的终产物且关键酶苯丙氨酸氨裂解酶(PAL)的活性通过反馈机制得到了提高。不过，由于CHS和F3H持续受到抑制这一事实，所以不能形成这些黄酮类化合物的终产物且结果是luteoliflavan、北美圣草素和其它酚类的形成得到了增加(附图1)。
因为黄烷酮3-羟化酶(F3H)的酶活性降低，所以黄酮类化合物北美圣草素、原花色素类(3位C原子上被氢取代)例如luteoforol、luteoliflavan、apigeniflavan和tricetiflayan以及上述结构相关物质的同源和异源寡聚体和聚合物的产量提高。
当植物中黄烷酮3-羟化酶(F3H)的酶活性降低之后，发现了高浓度的酚类羟基肉桂酸(对羟基肉桂酸、阿魏酸、芥子酸)、水杨酸或繖形酮、包括由它们形成的同源和异源寡聚体和聚合物。诸如(例如)根皮素这样的查耳酮的浓度和诸如(例如)白藜芦醇这样的茋类的浓度同样得到了提高。
由于黄烷酮3-羟化酶(F3H)的酶活性降低，所以黄酮类、酚类化合物、查耳酮类和芪类的糖苷的浓度也得到了提高。
根据这些发现和由此而得的推论，生产出遗传修饰的农作物植物，其中通过反义构建物在完整植物或各个植物器官或植物组织中完全或部分、永久或短暂地降低了F3H的活性，使得治疗、保健或滋补用成分的含量在数量和质量上均得到了改善。
可以将本发明通过以反义方向表达黄烷酮3-羟化酶而用于增加黄酮类化合物和酚类化合物含量的方法成功地用于下列农作物植物，但该方法并不限于所述的植物：葡萄树、樱桃、番茄、李子、黑刺李、乌饭树(Blaubeere)、草莓、桔果(诸如柑橘、葡萄柚)、木瓜、红球甘蓝(Rotkohl)、嫩茎花椰菜(Broccoli)、抱子甘蓝(Rosenkohl)、可可豆、羽衣甘蓝(Grünkohl)、胡萝卜、欧芹、芹菜、洋葱、大蒜、茶、咖啡、啤酒花、大豆、油菜、燕麦、小麦、黑麦、黑果腺肋花楸(Aronia melanocarpa)、银杏。
此外，本发明涉及用本发明方法生产的具有高含量黄酮类化合物和酚类成分并具有降低的黄烷酮3-羟化酶的酶活性的植物。
另一种生产通过反义技术降低黄烷酮3-羟化酶活性的植物的替代方法是，使用从文献中得知的其它分子遗传学方法诸如共抑制或特异性抗体的表达以便实现这一作用。
此外，本发明涉及用本发明方法生产的植物或这些植物的部位用作食品、食品添加剂或用于生产人和动物的治疗用组合物、保健用组合物或滋补用组合物(汁、茶、提取物、发酵产品)和生产化妆品的用途。
令人意外的是，目前已经发现按照本发明生产的植物或这些植物的部位或由它们产生的产品(茶、提取物、发酵产品、汁等)具有下列作用：
(1)体外抗氧化能力(电子自旋共振(ESR)、LDL氧化、总体抗氧化能力、NO清除)得到改善；
(2)观察到了对酶类、特别是信号转导酶类(蛋白激酶C、酪氨酸蛋白激酶、磷脂酰肌醇3-激酶)的调制作用；
(3)在内皮细胞、淋巴细胞和平滑肌细胞中诱导氧化还原敏感性转录因子(NF-kB、AP-1)的调制作用；
(4)涉及炎症疾病病理(细胞因子IL-1和IL-8、巨噬细胞趋化蛋白1(MCP-1)、粘着因子ICAM-1和VCAM-1)的靶基因的基因表达的调节作用得到了调制；
(5)诱导了抗聚集作用；
(6)抑制了肝细胞中的胆固醇合成；
(7)存在抗增殖/抗肿瘤作用。
实施例1
从番茄(Lycopersion esculentum Mill.cv.Moneymaker)中克隆黄烷酮3-羟化酶的基因
将番茄(Lycopersion esculentum Mill.cv.Moneymaker)的成熟果实洗涤、干燥并使用无菌刀片将果皮与种子、中柱和木质部分离。将果皮(约50g)冷冻在液氮中。然后，在掺合机中粉碎该物质。在预冷却的研钵中，用100ml匀化培养基处理粉碎的物质并混合。接着将混悬液通过无菌纱布压榨而转入离心瓶中。接下来加入1/10个体积的10％SDS并剧烈混合所述物质。在冰上放置10分钟后，加入1个体积的苯酚/氯仿并将离心瓶密封且剧烈混合内含物。以4000rpm离心15分钟后，将上清液转入新反应容器中。随后进行三次以上的苯酚/氯仿提取和一次氯仿提取。然后，加入1个体积的3M NaAc和2.5个体积的乙醇。在-20℃下将核酸沉淀过夜。第二天早晨，在冷冻离心机(4℃)中以10,000rpm将核酸沉淀15分钟。弃去上清液并将沉淀重新悬浮于5-10ml的3M冷NaAc中。将该洗涤步骤重复两次。将沉淀用80％乙醇洗涤。当完全干燥时，将沉淀溶于约0.5ml的无菌DEPC水并用光度法测定RNA浓度。
首先用3.3μl的3M乙酸钠溶液、2μl的1M硫酸镁溶液处理20μg的总RNA并用DEPC水将所得混合物制成100μl的终体积。向该体系中加入1微升不含RNase的DNase(Boehringer Mannheim)并在37℃下将该混合物培养45分钟。通过用苯酚/氯仿/异戊醇振摇提取而除去酶后，用乙醇沉淀RNA并将沉淀溶于100μl DEPC水。使用cDNA试剂盒(Gibco BRL)将来自该溶液中的2.5μg的RNA转录成cDNA。
使用来源于编码黄烷酮3-羟化酶的cDNA克隆的氨基酸序列鉴定了初级序列中的保守区(Britsch等Eur.J.Biochem.217,745-754(1993))，而它们可用作设计简并PCR寡核苷酸的基础。使用肽序列SRWPDK(碧冬茄(Petunia hybrida)序列FL3HPETHY中的147-152位氨基酸)测定5’寡核苷酸且它具有下列序列：
5’-TCI(A/C)G(A/G)TGG CC(A/C/G)GA(C/T)AA(A/G)CC-3。
通过使用肽序列DHQAVV(碧冬茄序列FL3HPETHY中的276-281位氨基酸)推定的寡核苷酸序列如下：5’-CTT CAC ACA(C/G/T)GC(C/T)TG(A/G)TG(A/G)TC-3 。
使用Perkin-Elmer的tTth聚合酶、按照制造商的说明进行PCR反应。所用的模板是1/8的cDNA(相当于0.3μg的RNA)。PCR程序如下：
30个循环：
94℃4秒；
40℃30秒；
72℃2分钟；
72℃10分钟。
按照制造商的说明将片段克隆入Promega’s载体pGEM-T中。
通过测序来检验该片段的正确性。使用存在于载体pGEM-T的多接头中的限制切割位点NcoⅠ和PstⅠ分离PCR片段并使用T4-聚合酶使突出端钝端化。将该片段克隆入SmaⅠ-(钝端化)切割载体pBinAR(Hfgen和Willmitzer,PlantSci.66:221-230(1990))中(参见附图2)。该载体含有CaMV(花椰菜花叶病毒)35S启动子(Franck等，Cell 21:285-294(1980))和来自章鱼氨酸合酶基因的终止信号(Gielen等，EMBO J 3:835-846(1984))。这种载体在植物中介导对抗菌素卡那霉素的耐受性。所得的DNA构建体中含有有义和反义方向的PCR片段。将所述的反义构建体用于生产转基因植物。
附图2：片段A(529bp)含有CaMV 35S启动子(花椰菜花叶病毒的6909-7437位核苷酸)。片段B含有反义方向的F3H基因片段。片段C(192bp)含有章鱼氨酸合酶基因的终止信号。
使用5’RACE系统克隆来自番茄(Lycopersion esculentum Mill.cv.Moneymaker)的黄烷酮3-羟化酶的较长cDNA片段。
因用于反义构建体的F3H PCR片段的尺寸较小，未能成功地产生具有降低的F3H的mRNA瞬变平衡量的植物。为了排除这一情况，应使用较长F3H片段生产第二种反义构建体。
将5’RACE法(用于快速扩增cDNA末端的系统)用于克隆较长的F3H片段。
通过将5’RACE系统(Life TechnologiesTM的2-0版)用于快速扩增cDNA末端的5’RACE法来延伸F3H PCR片段。
总RNA分离自番茄(Lycopersion esculentum Mill.cv.Moneymaker)的成熟番茄果实(参见上文)。
使用GSP-1(基因特异性引物)5’-TTCACCACTGCCTGGTGGTCC-3’、按照制造商的说明进行cDNA的第一链合成。在RNase消化后，使用Life TechnologiesTM的GlassMAx自旋系统、按照制造商的说明纯化cDNA。
使用末端脱氧核苷酸转移酶将细胞因子均聚物加入到纯化的单链F3H cDNA的3’末端上。
使用结合在GSP-1识别序列3’区上游的第二种基因特异性引物(GSP-2)扩增5’-延长的F3H cDNA且由此使“嵌套式”PCR得以进行。所用的5’引物是“5’RACE缩短的锚定引物”，它由制造商提供且与cDNA的均聚化dC尾互补。
将如此扩增称作F3H延长的的cDNA按照制造商的说明克隆入Promega’s载体pGEM-T中。
通过测序证明所述cDNA的同一性。
使用存在于载体pGEM-T的多接头中的限制切割位点NcoⅠ和PstⅠ分离F3H延长的的cDNA片段并使用T4-聚合酶使突出端钝端化。将该片段克隆入SmaⅠ-(钝端化)切割载体pBinAR(Hfgen和Willmitzer,1990)中(参见附图3)。该载体含有CaMV(花椰菜花叶病毒)35S启动子(Franck等，1980)和来自章鱼氨酸合酶基因的终止信号(Gielen等，1984)。这种载体在植物中介导对抗菌素卡那霉素的耐受性。所得的DNA构建体中含有有义和反义方向的PCR片段。将所述的反义构建体用于生产转基因植物。
附图3：片段A(529bp)含有CaMV 35S启动子(花椰菜花叶病毒的6909-7437位核苷酸)。片段B含有反义方向的F3H基因片段。片段C(192bp)含有章鱼氨酸合酶基因的终止信号。
实施例2
表达反义方向黄烷酮3-羟化酶亚片段的转基因番茄(Lycopersion esculentum Mill.cv.Moneymaker)的生产
所用的方法是Ling等在Plant Cell Report 17,843-847(1998)中所述的方法。在约22℃下用16-小时光照/8-小时黑暗方式进行培养。
通过在4％浓度的次氯酸钠溶液中培养10分钟来对番茄种子(Lycopersicon esculentum Mill.cv.Moneymaker)进行灭菌，且随后用无菌蒸馏水洗涤3-4次并置于用3％蔗糖、pH 6.1补充的MS培养基上用于发芽。在发芽时间达7-10天后，备好子叶用于转化。
第1天：用1.5ml约10日的烟草混悬液培养物覆盖含有“MSBN”培养基的培养皿。将平板用薄膜覆盖并在室温下培养至第2天为止。
第2天：以不形成气泡的方式将无菌滤纸置于用烟草混悬液培养物覆盖的平板上。将切成十字形的子叶置于滤纸的上部朝下处。在培养室内将培养皿培养3天。
第5天：将农杆菌培养物(LBA4404)通过以约3000g离心10分钟来沉淀并重新悬浮于MS培养基中以使OD为0.3。将子叶部分放入这种混悬液并在室温和缓慢振摇下培养30分钟。然后，将子叶部分在无菌滤纸上进行一定的干燥并放回其原始平板以便在培养室内持续培养3天。
第8天：将共培养的子叶部分置于MSZ2K50+β上并在培养室内再培养4周。然后将它们进行传代培养。
将形成的苗转入根诱导培养基中。
在成功地生根后，测试该植物并转入温室。
实施例3
原代大鼠肝细胞培养物中胆固醇生物合成的抑制
储备溶液的制备
将含有A)仅天然黄烷酮3-羟化酶基因(对照)和B)如实施例2中所述，另外含有反义方向的黄烷酮3-羟化酶亚片段的10-20mg成熟番茄cv.“Moneymaker”冻干物确切称重，并用得到10mM总黄酮类化合物储备溶液的量的DMSO处理。在本试验开始前立即制备这些储备溶液的培养基稀释液。进行10-4-10-8M的10倍稀释步骤。
肝细胞培养物的制备
通过灌注胶原酶而从雄性Sprague-Dawley大鼠(240-290g)获得原代肝细胞(Gebhardt等，Arzneimittel-Forschung/Drug Res.41:800-804(1991)1990)。以125,000细胞/cm2的细胞密度在胶原蛋白包被的培养皿(6-孔平板，Greiner,Nürtingen)内补充了10％小牛血清的Williams培养基E中培养肝细胞。Gebhardt等在CellBiol.Toxicol.6:369-372(1990)且Mewes等在Cancer Res.53:5135-5142(1993)中发现了特别是在培养基上的更具体的情况。2小时后，将培养物转入不含血清的补充了0.1μM胰岛素的培养基中。再进行20小时后，将它们用于本试验。在每种情况中，在来自2-3只大鼠的三份独立的培养物中检测测试物质。
用测试物质A和B培养肝细胞培养物。
为了证明胆固醇的生物合成受到测试物质A和B的影响，将肝细胞培养物总计保持22小时。然后，将它们与补充了14C乙酸盐(仅微量)的不含血清的Williams培养基E以及在指定浓度下的测试物质一起培养2小时。在每一系列试验中均包括对照组。方法如Gebhardt(1991)和Gebhardt在Lipids 28；613-619(1993)中具体描述。微量14C乙酸盐快速与胞内乙酰辅酶A集合体互换且由此将14C乙酸盐混入由＞90％胆固醇组成的可以按照可靠方式测定的固醇部分中(Gebhardt,1993)。
用于影响胆固醇生物合成的分析方法
通过Gebhardt(1991)的方法测定混入固醇部分(非水解的脂类)中的14C乙酸盐。在所用的应用Extrelut柱(Merck,Darmstadt)的提取方法中，除去95％以上的14C乙酸盐(和由它形成的小量的其它低分子量代谢物)。本试验要求在测试物质作用下进行胆固醇与前体固醇类的相对合成率之间的比较(Gebhardt,1993)。
肝细胞培养物的视觉和微生物质量检测
在培养试验之前和之后，对所用的所有培养物在显微镜下以可见方式检验微生物的污染情况和细胞单层的完整性。在任意样品中没有观察到细胞形态上的可识别的改变(特别是在高浓度下)。这基本上不包括由测试物质的细胞毒性作用影响的试验结果。
对所有培养物进行的常规无菌试验显示无论在何种情况下都没有微生物污染的痕迹。
结果
来自未经遗传修饰的(对照组)番茄的样品A)无论在何种情况下都没有显示出对胆固醇生物合成的作用。相反，来自含有反义方向黄烷酮3-羟化酶亚片段的番茄的样品B显著抑制了胆固醇的生物合成。
Claims (5)
1．一种增加植物中黄酮类化合物和酚类成分的含量的方法，其中通过分子遗传学方法来生产植物，其中降低了黄烷酮3-羟化酶的活性。
2．一种如权利要求1中所述用于增加植物中黄酮类化合物和酚类成分的含量的方法，其中通过分子生物学方法(例如反义构建物、共抑制、表达特异性抗体或表达特异性抑制剂)在完整植物或植物部位中完全或部分、永久或短暂地降低了黄烷酮3-羟化酶的活性。
3．一种如权利要求1或2中所述的方法，其中所述的植物是葡萄树、樱桃、番茄、李子、黑刺李、乌饭树、草莓、桔果(诸如柑橘、葡萄柚)、木瓜、红球甘蓝、嫩茎花椰菜、抱子甘蓝、可可豆、羽衣甘蓝、胡萝卜、欧芹、芹菜、洋葱、大蒜、茶、咖啡、啤酒花、大豆、油菜种子、燕麦、小麦、黑麦、黑果腺肋花楸、银杏。
4．一种通过权利要求1-3中任意一项所述方法生产的具有高含量黄酮类化合物和酚类成分的植物，其中降低了黄烷酮3-羟化酶的酶活性。
5．通过权利要求1-3中任意一项所述方法生产的植物或这些植物部位用作食品、食品添加剂或用于生产人和动物的治疗用组合物、保健用组合物或滋补用组合物(汁、茶、提取物、发酵产品)和生产化妆品的用途。
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| CN102481000A (zh) * | 2009-04-21 | 2012-05-30 | J.I.哈斯 | 动物饲料组合物和饲喂方法 |
| CN102573503A (zh) * | 2009-07-29 | 2012-07-11 | 雀巢产品技术援助有限公司 | 含有黄烷酮的食品组合物 |
| WO2015140589A1 (en) * | 2014-03-20 | 2015-09-24 | Hongkong Chuanghui International Limited | Method for preparation multifunctional liquid medicament from vegetable feedstock, and the product produced by the method |
| CN105985936A (zh) * | 2015-02-02 | 2016-10-05 | 中国人民解放军第二军医大学 | 灯盏花黄烷酮-3-羟化酶及其编码基因与应用 |
| CN112391362A (zh) * | 2020-11-04 | 2021-02-23 | 江南大学 | 催化活性提高的黄酮3β-羟化酶突变体及其应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100642939B1 (ko) * | 2003-02-11 | 2006-11-10 | 학교법인 신천학원 | 자두추출물을 함유하는 화장비누 및 그 추출방법 |
| JP2007520230A (ja) * | 2004-02-06 | 2007-07-26 | コンク ユニヴァーシティ インダストリアル コーペレーション コープ | 高濃度イソフラボンを含む発芽豆及びその製造方法 |
| KR100553522B1 (ko) * | 2004-02-06 | 2006-02-20 | 학교법인 건국대학교 | 이소플라본 강화 발아 녹두 및 그 제조방법 |
| KR100663669B1 (ko) * | 2005-05-18 | 2007-01-02 | 금호석유화학 주식회사 | 배유 내에 높은 농도의 플라보노이드를 생산하는 형질전환쌀 |
| WO2013183177A1 (ja) * | 2012-06-07 | 2013-12-12 | 株式会社燦樹 | ニンニク卵黄組成物及びその製造方法 |
| KR101415687B1 (ko) * | 2012-09-19 | 2014-07-10 | 농업회사법인 호트팜 주식회사 | 조직배양기술을 이용한 아로니아의 줄기마디배양으로부터 유식물체의 대량 증식방법 |
| CN111875689B (zh) * | 2020-08-07 | 2022-02-01 | 山东玄康种业科技有限公司 | 一种利用番茄绿茎紧密连锁标记创制雄性不育系的方法 |
| EP4206192A1 (en) | 2020-08-25 | 2023-07-05 | Otsuka Pharmaceutical Co., Ltd. | Kaempferol aglycone-containing extract |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5432068A (en) * | 1990-06-12 | 1995-07-11 | Pioneer Hi-Bred International, Inc. | Control of male fertility using externally inducible promoter sequences |
| ATE226981T1 (de) * | 1992-03-09 | 2002-11-15 | Univ Washington | Methoden zur regulation der früchtbarkeit von pflanzen |
| GB9525459D0 (en) * | 1995-12-13 | 1996-02-14 | Zeneca Ltd | Genetic control of fruit ripening |
| AU2766099A (en) * | 1998-02-25 | 1999-09-15 | E.I. Du Pont De Nemours And Company | Plant flavanone-3-hydroxylase |
| AU2687000A (en) * | 1999-02-22 | 2000-09-14 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Transgenic plants and method for transforming carnations |
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1999
- 1999-06-17 DE DE19927574A patent/DE19927574A1/de not_active Withdrawn
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2000
- 2000-06-07 WO PCT/EP2000/005257 patent/WO2000078980A1/de not_active Application Discontinuation
- 2000-06-07 CA CA002340319A patent/CA2340319A1/en not_active Abandoned
- 2000-06-07 JP JP2001505720A patent/JP2003503032A/ja not_active Withdrawn
- 2000-06-07 EP EP00945714A patent/EP1102855A1/de not_active Withdrawn
- 2000-06-07 HU HU0103307A patent/HUP0103307A2/hu unknown
- 2000-06-07 KR KR1020017002018A patent/KR20020068256A/ko not_active Application Discontinuation
- 2000-06-07 AU AU59704/00A patent/AU5970400A/en not_active Abandoned
- 2000-06-07 CN CN00801147A patent/CN1314943A/zh active Pending
- 2000-06-07 PL PL00346059A patent/PL346059A1/xx not_active Application Discontinuation
- 2000-06-07 IL IL14117300A patent/IL141173A0/xx unknown
- 2000-06-07 BR BR0006869-1A patent/BR0006869A/pt not_active Application Discontinuation
- 2000-06-15 CO CO00044702A patent/CO5280139A1/es not_active Application Discontinuation
- 2000-06-16 AR ARP000103001A patent/AR024381A1/es unknown
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2001
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102481000A (zh) * | 2009-04-21 | 2012-05-30 | J.I.哈斯 | 动物饲料组合物和饲喂方法 |
| CN102481000B (zh) * | 2009-04-21 | 2015-07-29 | J.I.哈斯 | 动物饲料组合物和饲喂方法 |
| CN102573503A (zh) * | 2009-07-29 | 2012-07-11 | 雀巢产品技术援助有限公司 | 含有黄烷酮的食品组合物 |
| WO2015140589A1 (en) * | 2014-03-20 | 2015-09-24 | Hongkong Chuanghui International Limited | Method for preparation multifunctional liquid medicament from vegetable feedstock, and the product produced by the method |
| CN105985936A (zh) * | 2015-02-02 | 2016-10-05 | 中国人民解放军第二军医大学 | 灯盏花黄烷酮-3-羟化酶及其编码基因与应用 |
| CN112391362A (zh) * | 2020-11-04 | 2021-02-23 | 江南大学 | 催化活性提高的黄酮3β-羟化酶突变体及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1102855A1 (de) | 2001-05-30 |
| JP2003503032A (ja) | 2003-01-28 |
| IL141173A0 (en) | 2002-02-10 |
| CO5280139A1 (es) | 2003-05-30 |
| AU5970400A (en) | 2001-01-09 |
| BR0006869A (pt) | 2001-08-07 |
| KR20020068256A (ko) | 2002-08-27 |
| WO2000078980A1 (de) | 2000-12-28 |
| ZA200101328B (en) | 2002-02-18 |
| DE19927574A1 (de) | 2000-12-21 |
| AR024381A1 (es) | 2002-10-02 |
| CA2340319A1 (en) | 2000-12-28 |
| BG105246A (bg) | 2001-10-31 |
| HUP0103307A2 (hu) | 2001-12-28 |
| PL346059A1 (en) | 2002-01-14 |
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