CN101472574B - 睾丸酮增强剂 - Google Patents
睾丸酮增强剂 Download PDFInfo
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- CN101472574B CN101472574B CN2007800233762A CN200780023376A CN101472574B CN 101472574 B CN101472574 B CN 101472574B CN 2007800233762 A CN2007800233762 A CN 2007800233762A CN 200780023376 A CN200780023376 A CN 200780023376A CN 101472574 B CN101472574 B CN 101472574B
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Abstract
本发明提供了一种增加睾丸酮水平的物质，其是一种更安全的并且更常规消费的食物成分。本发明的睾丸酮增强剂含有作为活性成分的维生素K。该维生素优选为甲萘醌类-4和/或甲萘醌类-7。这种增强剂作为制药剂、补充剂、保健食品或功能性食品用来预防、改善、和/或治疗由减少的睾丸酮引起的症状或疾病而有用。
Description
技术领域
本发明涉及一种睾丸酮增强剂。特别地，本发明涉及一种增强内源性睾丸酮的合成物。
背景技术
睾丸酮是一种典型的雄性激素，广泛地促进肌肉生长、认知功能、血管柔软性、脂类代谢、生殖功能、等等。虽然睾丸酮的分泌随年龄的增长而减少，内分泌的破坏因素的存在也会影响分泌。最近的，在极端的维生素K不足状态下无菌鼠的DNA微点阵分析表明了甲萘醌类-4促进睾丸酮生物合成的可能性(非专利文件1和2)。
结果表明，当睾丸酮分泌减少时，集中力和意欲也减退。记忆力变弱，同时力量、排尿、和男性性功能也恶化。在近几年中，遭受男性更年期混乱痛苦的患者增加了。在男性更年期混乱中，作为性腺机能减退的结果，血液睾丸酮水平会下降，这引起了例如上面表述的症状。
一种对男性更年期混乱的治疗是激素代替疗法，其中患者被注射睾丸酮方剂。然而，该注射引起了血液睾丸酮水平的迅速提高，并且事实上可能引起疾病。激素水平的迅速提高可能引起影响前列腺、血管、肝、肺、等等的不利的副作用。因此，激素代替疗法有时使用经皮肤起作用的蒙皮补片，通过其缓慢释放睾丸酮。
除如上所述的从外部被代替的睾丸酮，下面的方法用来提高体内睾丸酮的水平：在玛卡(maca)等等中找到的苯甲基葡糖异硫氰酸盐和异硫氰酸苄酯的摄入(专利文件1)；玛卡(maca)和鹿角的混合物的摄入(专利文件2)；和取代的吡唑化合物的摄入(专利文件3) 非专利文件1：第八届维生素K和骨骼会议记录，87-89页，2005-12-10，Eisai Co.，Ltd. 非专利文件2：白川，等，生物化学生物物理学学报，通过小鼠中胆固醇侧链裂解酶Cyplla的减量调节，维生素K缺乏降低了睾丸中睾丸酮产物，正在评论中的文章，已经接受的原稿，2006.6.6在线可得。(Shirakawa，et al.，Biochim.Biophys.Acta Vitamin K deficiency reduces testosterone production inthe testis through down-regulation of the Cyplla a cholesterol side chain cleavageenzyme in rats，ARTICLE In Press，Accepted Manuscript，Available online 6，June2006) 专利文件1：日本专利申请书-公开号2005-306754 专利文件2：日本专利申请书-公开号2003-523945 专利文件3：日本专利申请书-公开号2005-504093
发明内容
上述达到睾丸酮增强作用的合成物是天然药物或者化学合成药物。虽然增加血液睾丸酮水平的通常消费的、安全的食品成分或营养素是优选的，但是这样的物质并不是现在已知的。因此，需要一种增加睾丸酮水平的更安全的和更常用的食品成分的物质。
发明者发现，通过食物摄入的维生素K1或维生素K2可以转换成组织中的甲萘醌类-4。由于睾丸中有特别高浓度的甲萘醌类-4，发明者试图确定睾 丸中维生素K的功能。通过这些研究，发明者发现血液睾丸酮水平可以通过摄入维生素K而提高，从而达到本发明的目的。换句话说，本发明提供了一种包含维生素K的睾丸酮增强剂。
维生素K提供的传统的已知功能包括维持正常的血液凝固，增强骨形成，控制骨吸收，通过预防动脉煤化而预防动脉硬化，以及治疗肝脏疾病。维生素K可以引起雌激素水平的提高是根本未知的。虽然非专利文件1和2提出维生素K有助于睾丸酮的生物合成，但是通过维生素K给药达到睾丸酮的增加是不能预知的。
上述的维生素K优选为维生素K2。
上述的维生素K更优选为甲萘醌类-4和/或甲萘醌类-7。
本发明提供由上述睾丸酮增强剂制得的药物，其可以预防、改善、和/或治疗由减少的睾丸酮引起的症状和疾病。
本发明还提供了添加了睾丸酮增强剂的补充物、保健食品和功能性食品。
在本发明中，血液睾丸酮水平可以通过对人高度安全的维生素K的摄入而轻易地增加。因为水溶性维生素K比传统的睾丸酮方剂在体内更容易积累，所以效果也更长效。作为回到普通水平的睾丸酮水平的结果，维生素K促成的功能(肌肉强度，性功能，等等)可以被维持或改善。选择性地，例如因为减少的睾丸酮引起的男性更年期紊乱的症状和疾病可以被改善。本发明的睾丸酮增强剂可以容易地以功能性食品或保健食品被消费。因此，上述症状和疾病的预防是可以实现的。
虽然一个人每日所需的维生素K的摄入是55μg-80μg(日本人饮食参考摄入，2005)，但是可容许的上限摄入水平是30mg的非常高的水平。维生素K是一种非常安全的物质。因此，本发明的睾丸酮增强剂比传统已知的睾丸酮增强剂在安全性上更优秀。
附图简要说明
【附图1】当小鼠按实施例1被给与MK-4饮食、以及作为比较实施例的对照饮食和低维生素K饮食时，小鼠睾丸中维生素K类似物浓度的比较图。 【附图2】附图1中小鼠中的P450scc mRNA表达水平的比较图。 【附图3】附图1中小鼠中的P450scc蛋白质水平的比较图。 【附图4】附图1中小鼠中的血浆睾丸酮浓度的比较图。 【附图5】当小鼠按实施例2被给与维生素K1添加的饮食组，以及作为比较实施例的对照饮食组时，小鼠的体重日变化图。 【附图6】附图5中小鼠的摄入量的日变化图。【附图7】附图5中小鼠中的睾丸维生素K浓度比较图。 【附图8】附图5中小鼠中的血液睾丸酮值的变化图。 【附图9】附图5中小鼠中的睾丸睾丸酮浓度的比较图。
实现本发明的最佳模型
根据本发明的一个具体实施方案的一种睾丸酮增强剂将被详细描述。本发明的睾丸酮增强剂中使用的维生素K是维生素K1、维生素K2、和维生素K3。在绿色和黄色蔬菜、豆类、植物油、海藻、海产、等等中发现具有高水平的维生素K1(也被认为是叶绿醌)。维生素K2(也被认为是甲萘醌类)通过微生物制备并且被发现在纳豆(日本发酵大豆)和例如干酪的乳制品中具有很高水平。肠道中的细菌也可以产生维生素K2。在维生素K2中，从甲萘醌类-4(MK-4) 到甲萘醌类-15(MK-15)的同系物依据萘醌部分的类异戊二烯侧链的长度而存在。例如，高水平的MK-6～MK-9在干酪中被找到，以及高水平的MK-7在纳豆中被找到。维生素K3(也被认为是亚硫酸氢钠甲萘醌)是合成的。
当维生素K3在高水平被摄入时，副作用变成了一个关心的问题。因此，根据饮食经验，从蔬菜提取和精制的维生素K1，以及用纳豆杆菌等等从发酵物质提取的维生素K2是更安全的，并且，因此是优选的。可以廉价并且容易地被制备的维生素K2是更优选的。许可作为食品添加剂的甲萘醌类-4和/或用作食品成分的甲萘醌类-7是尤其优选的。通过食物摄入的维生素K1和维生素K2已知可以在体内转化为甲萘醌类-4。
各维生素K的制备方法不被特别限制。商业上可得的产品也可以不受限制地被使用。特别地，使用微生物的发酵、从食品中的提取和精制、以及化学合成都可以被使用。
维生素K1使用已知的方法(例如日本专利申请书-公开号H5-155803)从绿色紫苏属，紫苏属，mulukhiya，parsely，食用菊花叶，野油菜(日本菘菠菜)，菠菜，mitsuba(日本野生parsely)，榛子叶，榛实出发，栗子叶，大麦幼芽，燕麦幼芽，卷心菜，茎椰菜，花椰菜，番茄，植物油(大豆油，菜籽油，芝麻油，花生油，玉米油，红花油，向日葵油，米糠油，和橄榄油)等等提取和精制。维生素K1可以通过合成获得。维生素K1是亮黄色的、热稳定的但是对光不稳定的脂溶性油。维生素K可以是一种氧化物形式。
维生素K2通过使用例如纳豆杆菌的微生物，使用在日本专利申请书-公开号H08-073396，H-11-92414，H-10-295393，2001-136959，等等中描述的方法发酵制备。
包含在本发明的睾丸酮增强剂中的维生素K含量依据摄入的合成为的量而变化。该含量按重量计通常在0.0001％-100％的范围内，优选按重量计0.001％-90％，更优选按重量计0.01％-70％，以及甚至更优选按重量计1％-50％。当含量少于0.0001％时，要达到睾丸酮增强效果需要的量将不能摄取。
除必要成分维生素K以外，本发明的睾丸酮增强剂可以包含一种或更多种类型的已知增加睾丸酮的物质。该物质是，例如，例如玛卡(maca)的植物，例如鹿角的天然药物，来自这些植物和天然药物的提取物，苯甲基硫代葡萄糖酸盐，苯甲基异硫氰酸盐，以及取代吡唑化合物。
除必要成分维生素K、和适当的睾丸酮增强物质以外，本发明的睾丸酮增强剂可以包含药理学可用的载体、附型剂、助剂，等等，它们的使用量在其剂量不抑制本发明作用的范围内。
特别的，可以包含以下物质：例如乳糖、蔗糖、果糖、葡萄糖、葡萄糖水合物、白糖、精制蔗糖、赤藓醇、木糖醇、山梨糖醇、甘露醇、巴拉金糖、palatinit、粉状还原麦芽糖、淀粉糖浆、羧甲醚纤维素、糊精、玉米淀粉、预胶凝淀粉、部分预胶凝淀粉、马铃薯淀粉、羟丙基淀粉、氨基酸，高岭土，硅酸酐、硅酸、硅酸铝、碳酸氢钠、磷酸钙、磷酸二氢钙、碳酸钙、氧化镁，氢氧化铝、脂肪酸、脂肪酸盐、脂肪酸单酸甘油酯和脂肪酸甘油二酯、乙醇、植物油、橄榄油、大豆油、玉米油、脂肪油、油剂和脂肪、粘性石蜡、丙二醇、乙二醇、聚乙二醇、和甘油的载体和附型剂；例如微晶纤维素、微晶纤维素羧甲醚纤维素钠、甲基纤维素、羟丙纤维素、低取代羟丙纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素醋酸琥珀酸、羧甲醚纤维素钠、乙基纤维素、羧甲基乙基纤维素、羟乙基纤维素、小麦淀粉、米淀粉、玉米淀粉、马铃薯淀粉、预胶凝淀粉、部分预胶凝淀粉、羟丙基淀粉、糊精、出芽短梗孢糖、聚乙烯吡咯烷酮、烷基氨基异丁烯酸共聚物E、烷基氨基的异丁烯酸共聚 物RS、甲基丙烯酸共聚物L、甲基丙烯酸共聚物、聚乙烯醇缩醛二乙氨基醋酸盐、聚乙烯醇、阿拉伯胶、阿拉伯胶粉、琼脂、明胶、白色虫胶、黄芪胶、和聚乙二醇的结合剂；例如小麦淀粉，米淀粉，玉米淀粉，合成铝矽酸盐，干燥氢氧化铝凝胶，硅酸镁铝酸盐，磷酸氢钙，无水磷酸氢钙，蜡，氢化植物油，聚乙二醇，轻质无水硅酸，合成铝矽酸盐，硬脂酸，聚乙二醇，滑石，硬脂酸镁，硬脂酸钙，水合二氧化硅，和蔗糖脂肪酸酯的润滑剂；例如微晶纤维素，甲基纤维素，低取代羟丙基纤维素，羧甲醚纤维素，羧甲醚纤维素钙，羧甲醚纤维素钠，交联羧甲基纤维素钠钠，小麦淀粉，米淀粉，玉米淀粉，马铃薯淀粉，部分预胶凝淀粉，羟丙基淀粉，羧甲基淀粉钠，和黄芪胶的崩解剂；例如大豆凝集素，蔗糖脂肪酸酯，聚乙二醇硬脂酸盐，聚氧乙烯氢化蓖麻油，聚氧乙烯聚丙二醇，去水山梨糖醇单油酸酯-去水山梨糖醇二油酸酯，去水山梨糖醇三油酸酯，单硬脂酸山梨糖醇酐酯，山梨聚糖甘油一棕榈酸酯，单月桂酸山梨醇酐酯，多山醇酯，单硬脂酸甘油酯，十二烷基硫酸钠，并且聚桂醇的表面活性剂；乳化剂；例如磷酸钠的助溶剂；吸收促进剂；例如盐酸、柠檬酸、柠檬酸钠、醋酸、酒石酸、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸钠和乳酸的pH调节剂；防腐剂；湿润剂；着色剂；调味剂；无痛剂；等等。
本发明的睾丸酮增强剂用于药物、补充剂、功能性食品、和保健食品。因此，该睾丸酮增强剂被加工成液体剂、粉末剂、颗粒剂、片剂、锭剂、糖浆剂，等等。因为维生素K是脂溶性的，该睾丸酮增强剂优选为片剂或锭剂形式。
本发明的睾丸酮增强剂在可以在例如面包、米饭、汤、预制食品、点心、和糖果的普通加工食品生产中被直接加入到其基础成分中。
本发明睾丸酮增强剂用于药物使用的给药方法没有特别限制。例如，口服法、经皮肤给药、输液、和注射(肌肉内、腹腔内、皮下注射、和静脉注射)都可以被使用。优选地，为了使患者压迫力更低，该睾丸酮增强剂以片剂或锭 剂形式口服摄取的。
本发明睾丸酮增强剂用于药物使用的剂量和用法可以通过考察患者表达的症状、患者的体重、给药间隔、给药方法、以及各种影响其它临床效应的因素而决定。典型地，成年男性的日常维生素K摄取量为10μg-100mg，优选地20μg-100mg。当维生素K用于治疗时，可以使用6mg-100mg。
当本发明的睾丸酮增强剂用于补充剂、功能性食品、保健食品、以及常规食品时，考虑到安全性，成年男性的日常维生素K摄取量为10μg-30mg，更优选地50μg-6mg。
除了人类，本发明的睾丸酮增强剂可以用于例如雄性家畜动物和宠物的动物的药物和功能性食品。给药的方法可以是非口服给药的，例如注射，以及口服给药的，例如通过功能性食品和配方饲养。
当包括人在内的哺乳动物摄取了本发明的睾丸酮增强剂、使用睾丸酮增强剂制备的药物、及包含有睾丸酮增强剂的食品，维生素K会增加睾丸酮。因此，本发明的睾丸酮增强剂被期望达到者用于原发性和继发性性腺机能减退，以及由衰老获环境因素引起的睾丸酮缺乏的治疗或预防药物的效果。本发明的睾丸酮增强剂可以预防、改善、和/或治疗各种由睾丸酮减少引起的疾病。特别地，肌肉、集中力、意欲、血管柔软性、脂类代谢、生殖功能、男性性功能、排尿功能，等等的退化的预防、改善、和/或治疗是被期待的。
接下来，本发明将使用实施列更详细地进行说明。但是，本发明不限于实施例。 【实施例1】 本发明的睾丸酮增强剂的血液睾丸酮增强效果通过使用普通小鼠进行研 究。普通小鼠是甚至当饲料不包含维生素K时极端的维生素K缺乏症也没有发生的小鼠，这是因为小鼠吸收了由其肠道细菌产生的维生素K。普通小鼠是用来推知到具有常规寿命的人类的模型。
(材料和方法) I 模型动物的制备 (饲养实验动物) 实验动物和饲养环境如下： 实验动物：普通小鼠(Wistar/Std，8周岁雄性) 饲养环境：在温度23℃、湿度50±5％、以及8AM点灯和8PM关灯的12小时明/暗循环的饲养室中饲养。
作为实验饮食组，提供以下三组： (1)低K饮食组(无维生素K添加) (2)对照饮食组(添加0.75mg/kg维生素K1) (3)MK-4添加饮食组(添加75mg/kg甲萘醌类-4) 这里，对照饮食中维生素K1的量是用于标准精制AIN93G饲料中的维生素K1浓度。因此，对照饮食组指的是包含通过常规小鼠饲料摄取的维生素K的量的标准饮食。添加到MK-4添加饮食组的甲萘醌类-4是四烯甲萘醌(NisshinPharma Inc.)
各实验饮食中，维生素K1或甲萘醌类-4(在本文内简称为“MK-4”)被加入以达到表1所示的组分比例，并且混合均匀。实验饮食使用的组分在表1中显示。 【表1】 实验饮食组成 *维生素K不添加到低K饮食组。7.5mg维生素K1添加到对照饮食组。750mgMK-4添加到MK-4添加饮食组。总量通过使用蔗糖调节到100g，形成维生素混合物。
在饲养方法中，预备饲养通过自由摄食和摄水饲养小鼠3-5天完成。商业可得的固体饲料(产品名：MR Labostock，Nosan Corp.)被使用。各实验饮食组包含在铁丝笼中集落饲养的4只小鼠。在预备饲养后，小鼠按照各自的实验饮食，自由摄食和摄水饲养35天。血液样品被获取，并且睾丸被摘除。
II 维生素K含量测定 (制备HPLC测定样品) 1g组织被精确测量并且放入塞住的棕色离心管中。2ml 66％的IPA溶液加入。然后样品在冰上在Polytron均质机(Biotron)中均质。均质期间，附着到管体的匀浆用3ml 66％的IPA冲洗并且加入到样品中。5ml己烷加入1ml含有作为内标物的9.96ng/ml或996ng/ml的MK-3的己烷溶液。该混合物振动5分钟然后萃取。
然后，该混合物被离心(4℃时3000rpm离心5分钟)，并且5ml上部的己烷层被分离置于一个棕色测试管中。分离的己烷层在减压情况下通过离心浓缩机进行浓缩。干的、固态己烷层再次溶解到2ml己烷中。该样品应用于事先用 10ml己烷-醚(96∶4，v/v)溶液和10ml己烷清洗的Sep-pak二氧化硅药液筒(Waters Corp.)。
药液筒用10ml己烷清洗以后，K基团用5ml己烷-醚(96∶4，v/v)溶液洗脱。混合物再次用离心浓缩机干燥以后，200μl(当使用996ng/ml的MK-3内标物时为2ml)乙醇加入到残基中，同时残基被溶解。颗粒用0.5μm过滤器(DISMIC03JP050AN，ADVANTEC)除去。滤过的混合物用作HPLC测定样品。
(HPLC测定条件) 制备的HOLC样品中的维生素K同系物是非荧光、氧化型的。当样品通过HPLC分离并且使用铂催化剂柱时，维生素K基团变成了荧光、还原型的。维生素K基团的数量取决于以HPLC还原荧光法，而该方法测量该样品的荧光浓度。 维生素K基团的数量取决于作为内标物的MK-3的相对数值。
(HPLC维生素K测定系统) 通过HPLC用于测定的维生素K测定系统如下： HPLC设备：Waters 600E System(Waters Corp.) 柱：Puresil C18，5μm，120A，4.6mm×50mm(Waters Corp.) 柱加热器：Column Heater(Bio-Rad Laboratories) 柱加热温度：50℃ 还原装置：铂还原柱IRICA-RC-10-1(IRICA Corp.) 荧光检测器：F-1000(Hitachi，Ltd.，检测波长Ex240nm，Em 430nm) 记录器：D-2000(Hitachi，Ltd.) 分析条件：流动相(8∶2)，流速1.0ml/min
在本方法中，HPLC还原荧光法被使用在通过使用铂催化剂柱将非荧光、氧化型维生素K基团变成荧光、还原型的维生素K基团中。维生素K基团的 荧光强度被测定。因此，移动相中有氧溶解对还原有不利的影响。溶解氧预先在减压情况下通过适合移动相的超声波除去。氮气(200ml/min或更多)从测定开始前2小时一直到测定完成始终被鼓入。
III RNA测定 (总RNA的制备) 约0.1g各单独小鼠的睾丸被放到专用的试管中。1ml作为RNA提取剂的ISOGEN(NIPPONGENE Co.，Ltd.)加入到试管中。混合物在Polytron均质机中均质。匀浆被转移到埃彭道夫试管中(eppendorftube)，并且在室温下保持5分钟。然后，200μl氯仿加入到匀浆中，同时该混合物用旋涡器剧烈搅动15秒钟。在混合物在静止下保持2-3分钟以后，混合物进行离心(13000rpm，4℃离心15分钟)，从而分成3层。只获取最上层。500微升的IPA加入到最上层。混合物上下轻微震荡，并且静置10分钟。
该混合物再次离心(13000rpm，4℃离心15分钟)。离心分离形成的沉淀用1000μl和500μl 75％的乙醇冲洗两次。沉淀用300μl DEPC-dH2O溶解。一部分溶解的沉淀用于吸光度测定(260nm和280nm)和琼脂糖凝胶电泳(0.7％TAE琼脂糖凝胶在150V进行35minutes)。RNA的浓度和纯度被测定。
(通过逆转录反应的cDNA的制备) 从各单体小鼠获得的RNA用DEPC-dH2O溶解至1μg/μl。RNA溶液分入2个PCR试管中，每个PCR试管含有4μl RNA溶液。一个试管制备用于RT(-)，其中逆转录酶没有加入，另一个用于检查是否含有染色体DNA。
1μl Oligo(dT)20(50μM)和1μl 10mM dNTPmix(dATP，dGTP，dCTP，和dTTP)加入到10μl DEPC-dH2O中形成的混合物注入到各试管中。这些试管放入到PCR循环变温加热器(TaKaRa Bio Inc.)并且在65℃下加热5分钟。
在加热并且随后在冰上放置1分钟或更长以后，试管被旋转减速。含有4μl5×First-Strand Buffer，1μl 0.1M DTT，0.5μl RNase OUT，和0.5μl Super Script III(dH2O被用于RT(-))的混合物加入到各试管中。试管再次被放入循环变温加热器，并且逆转录反应在50℃执行60分钟以及在70℃执行15分钟。因而获得cDNA样品。
(定量RT-PCR) 通过逆转录反应制备的已经稀释100倍的cDNA溶液用作样品。SYBRPremix Ex Taq(Perfect Real Time)(TaKaRa Bio Inc.)用作反应试剂。25μl(微升)SYBR Premix Ex Taq，1μl Rox Reference Dye，1.5μl正向引物和反向引物，和17μldH2O加入到4μl样品或标准cDNA。24μl上述反应溶液注入到MicroAmpOptical 96-well Reaction Plate(微安光学96槽反应板)的两个槽中，并且MicroAmp Optical 96-well Reaction Plate(微安光学96槽反应板)被插入到ABIPRISM 7000 Sequence Detection System(ABI PRISM 7000序列检测系统)中。
PCR反应循环为(60℃，2分钟)×1，然后(95℃，10分钟)×1，，然后(95℃，15秒钟到60℃，1分钟)×50。表2显示了用在定量RT-PCR中的引物序列(正向：序列编号1，反向：序列编号2) 【表2】
在这个方法中，GAPDH和真核起始因子1α1(EF-1)用作基因表的内标物基因。各基因的发现量通过基因发现量除以内表物基因发现量计算得到，并且显示为值为1的对照饮食组的相对数值。
IV 使用西部吸印技术的P450scc蛋白质水平测定 (生物组织样品和抗体) 解剖以后在-80℃储存的上述各组的睾丸被使用。抗P450scc抗体购自Chemicon International，Inc。
(组织匀浆制备) 当在1ml 1×磷酸盐缓冲生理盐水(PBS，含有10μl 100mM苯甲烷磺酰氟化物[PMSF])中冰冻时，0.2g睾丸在Polytron均质机(生物气候室)(Biotron)中均质。破碎的细胞通过睾丸在4℃，3000rpm离心5份分钟被除去。睾丸的上层清夜被收集以用作组织匀浆。一部分组织匀浆用于确定蛋白质数量。
(样品的SDS-处理) 100ml 3×SDS缓冲液(a)加入到200μl组织匀浆，并且样品在沸水浴中静置5分钟。随后SDS处理被执行。
(SDS-PAGE) 执行SDS处理的样品用3×SDS缓冲液稀释，此时蛋白质浓度为1μg/μl。然后15μl样品引入聚丙烯酰胺(b)，电泳(c)(100V，90分钟)被执行。
(传递) 电泳以后，浸渍在传递缓冲液中的3张3MM纸(Whatman Plc)、凝胶、ImmobilonTM(PVDF预先用甲醇和传递缓冲液均衡的传递薄膜[Millipore Corporation])、和3张3MM纸放置在阳极侧浸透的极板上，并且夹在极板之间。该套件随后被放在浸透槽(Bio-Rad Laboratories)中，同时传递被执行(250mA，180分钟)。
(阻滞) 传递完成以后，薄膜用TBS-T(e)冲洗并且在含有5％脱脂乳的TBS-T(脱脂乳溶液)阻滞1小时。
(抗体反应) 初次抗体反应在含有抗P450scc抗体(1/5000)的脱脂乳溶液执行1小时。第二次抗体反应在含有抗兔子IgG-HRP抗体(1/5000)的脱脂乳溶液中执行1小时。抗-β-肌动蛋白用作对照抗体。
(检测和分析) 1ml ECLTM西式印迹法检测试剂(Amersham Corp.)淋透整个薄膜。然后薄膜在黑暗中反应5分钟。发光标记用Las-1000显像系统(Fujifilm Corp.)获取，同是数量用ImageGauge(商标)图像处理软件确定。
(a)SDS缓冲液 70mM Tris-HCl(pH6.8)，33mM NaCl，1mM Na2EDTA，2％SDS(w/v)，40mMDTT，0.01％溴酚蓝(w/v)，and 10％甘油 (b)聚丙烯酰胺凝胶 分离胶：12.5％丙烯酰胺，375mM Tris-HCl(pH8.8)，0.1％SDS，0.05％TEMED，和0.075％APS(w/v) 浓缩胶：3.8％丙烯酰胺，125mM Tris-HCl(pH6.8)，0.1％SDS，0.05％TEMED，和0.075％APS(w/v) (c)电泳缓冲液 25mM Tris，0.19M甘氨酸，和0.1％SDS(w/v) (d)传递缓冲液 48mM Tris，39mM甘氨酸，和20％甲醇 (e)TBS-T缓冲液 0.1M Tris-HCl(pH7.5)，0.37M NaCl，和0.5％土温20
(组织匀浆中蛋白质定量分析) 组织匀浆中的蛋白质浓度用Bradford法测定。20微升适当稀释的样品溶液被放在埃彭道夫试管中。稀释5倍的1ml Bio-Rad蛋白质试料被加到样品溶液中并且用漩涡器混合。样品溶液在室温下静置5分钟以后，595nm时的吸光度被测定。牛血清白蛋白(BSA)作为标准曲线被使用。
V 睾丸酮测定 以下试剂盒用于测定 睾丸酮EIA试剂盒(Cayman Chemical Co.)
(样品制备) 因为血浆和睾丸匀浆中可能包含抑制测定的物质，所以类固醇激素预先用醚萃取。
(来自血浆的提取) 0.5ml血浆被放在测试管中。2.5ml二乙基乙醚加入到测试管，并且分离离心被执行(3000rpm，4℃，5minutes)。由离心分离形成的乙醚层(上层)被收集以后，2.5ml二乙基乙醚再次加入到血浆样品中，同时，相似的过程被执行。
收集的醚层在真空下使用离心真空浓缩器干燥(Taitec Corporation)。所得的 浓缩物溶解到0.5ml包含于试剂盒中的EIA缓冲液中。溶解的浓缩物用作血浆样品。
(来自睾丸的提取) 100mg睾丸组织在冰冻于5ml磷酸盐缓冲生理盐水时在Polytron均质机中均质。1ml匀浆被放入测试管。5ml二乙基乙醚加入到测试管并且用涡流器混合约1分钟，因而完成离心分离(3000rpm，4℃，5分钟)。
由离心分离形成的乙醚层(上层)被收集以后，5ml二乙基乙醚再次加入到睾丸匀浆中。收集的乙醚层在真空下用离心真空浓缩器干燥(Taitec Corporation)。所得的浓缩物溶解到1ml包含于试剂盒的EIA缓冲液中。溶解的浓缩物用作睾丸样品。
VI 统计分析 各组数据之间的差异通过一元配置方差分析检验以后，Scheffe多重比比较试验关于数据进行运行。
附图1显示了低K饮食(没有添加维生素K)、对照饮食(添加0.75mg/kg的维生素K)、和添加MK-4的饮食(添加75mg/kg的MK-4)给药35天的小鼠睾丸中维生素K1(右)和MK-4(左)的浓度结果。在所有实施例中，不管是何种给药形式，睾丸中的维生素K被证实已经转化为MK-4。虽然低K饮食组和对照饮食组之间没有观测到显著的差异，但是MK-4添加饮食组中的MK-4浓度非常高。
附图2显示了P450scc mRNA表达水平，P450scc mRNA是类固醇激素合成途径基因。相比对照饮食组和MK-4添加饮食组，低K饮食组中的表达水平显著较低。
附图3显示了P450scc蛋白质水平。对照饮食组和低K饮食组之间的变化没有观察到。然而，MK-4添加饮食组中的蛋白质水平显著较高。
附图4显示了血浆睾丸酮浓度。相比对照饮食组，MK-4添加饮食组中的血浆睾丸酮浓度显著较高。
从上述结果可知，通过服用维生素K，血液睾丸酮水平得以增加。对照饮食中维生素K浓度是必须的维生素K量，并且是可以通过常规饮食可以摄取的量。人们认为由于维生素K导致的睾丸酮水平下降很少发生。换句话说，根据本发明的积极摄取维生素K的结果，血液睾丸酮增加了。因此，当血液睾丸酮因为一些原因减少了，血液睾丸酮可以通过摄取维生K而增加。 【实施例2】 (材料和方法) 如实施例1中，实验动物和饲养条件是普通小鼠(Wistar/Std，8周大的雄性)在温度23℃、湿度50±5％、以及8AM点灯和8PM关灯的12小时明/暗循环的饲养室中饲养。
作为实验饮食组，以下3组被提供。 (1)对照饮食组(添加0.75mg/kg的维生素K1 (2)维生素K1添加饮食组(添加75mg/kg的维生素K1) (3)MK-4添加饮食组(添加75mg/kg的甲萘醌类-4) 维生素K1购自Wako Pure Chemical Industries，Ltd.购自Nisshin Pharma Inc.的甲萘醌类-4被使用。维生素K1或甲萘醌类-4加入到各实验饮食以表1中的组分比例并且均匀混合。
饲养期为35天。血液每周在18时从尾部静脉抽取。体重、饮食摄入、睾丸维生素K含量、睾丸睾丸酮浓度、以及血浆睾丸酮浓度被测定。分析方法与实施例相似。
(统计分析) 睾丸维生素K浓度和睾丸酮浓度的数据用Tukey法分析。血液中睾丸酮浓度随时间变化的分析通过二元排列方差分析(反复的)完成。在所有案例中，显著差异为P＜0.05。
(结果) 对照饮食组(添加0.75mg/kg的维生素K1)、维生素K1添加饮食组、以及MK-4添加饮食组之间的体重和饮食摄入的差异没有被观察到(附图5和附图6)。
附图7显示了睾丸维生素K浓度的结果(右：维生素K1，左：MK-4)。维生素K1添加饮食组和MK-4添加饮食组中的睾丸MK-4浓度显著增加。人们认为维生素K1在体内转化成为MK-4。
附图8显示了血液睾丸酮值的变化。维生素K1添加饮食组的血液睾丸酮值与对照饮食组的血液睾丸酮值在4周和5周时并未见不同。在2周和3周时，维生素K1添加膳食组的血液睾丸酮值比对照饮食组的血液睾丸酮值高。当全面的二元排列方差分析完成时，显著差异被确定为P＜0.01。
附图9显示了睾丸睾丸酮浓度的结果。维生素K1添加饮食组和MK-4添加饮食组的睾丸酮值都高。
从上述结果可知，维生素K1和维生素K2(menaquinone-4)可以增加血液睾 丸酮水平和睾丸睾丸酮水平。服用维生素K2是优选的。因为体重和饮食摄入的变化没有观察到，所以使用维生素K增加睾丸酮是一种安全的方法。
本发明优选的具体实施方案在上详细说明。然而，不用说，在本发明的范围以及本发明旨意内的变化和修改是可以被考虑到本申请中公开的本领域技术人员完成。本发明的具体实施方案如下： 1、一种含有作为活性成分的维生素K的睾丸酮增强剂。 2、根据上述条款1的睾丸酮增强剂，其中维生素K含量为按重量0.0001％-100％。 3、根据上述条款1的睾丸酮增强剂，其中上述维生素K是维生素K2。 4、根据上述条款1的睾丸酮增强剂，其中维生素K是甲萘醌类-4和/或甲萘醌类-7。 5、由含有作为活性成分的维生素K的睾丸酮增强剂制得的，预防、改善、和/或治疗由减少的睾丸酮引起的症状或疾病的药物。 6、根据上述条款5的药物，其中症状和疾病是肌肉、认知功能、集中力、意欲、血管柔软性、脂质代谢、生殖功能、男性性功能、和排尿功能的退化。 7、含有包含作为活性成分的维生素K的睾丸酮增强剂的补充剂、保健食品、和功能性食品。 8、根据上述条款7的补充剂、保健食品、和功能性食品，用于预防、改善和/或治疗肌肉、认知功能、集中力、意欲、血管柔软性、脂质代谢、生殖功能、男性性功能、和排尿功能的退化。 9、一种预防、改善、和/或治疗由减少的睾丸酮引起的症状或疾病的方法，包括服用有效剂量的含有作为活性成分的维生素K的睾丸酮增强剂。 10、根据上述条款9的方法，其中维生素K含量为按重量0.0001％-100％。 11、根据上述条款9的方法，其中上述维生素K是维生素K2。 12、根据上述条款9的方法，其中维生素K是甲萘醌类-4或甲萘醌类-7，或者其两者。 13、根据上述条款9的方法，其中症状和疾病是肌肉、认知功能、集中力、意欲、血管柔软性、脂质代谢、生殖功能、男性性功能、和排尿功能的退化。 14、用于制备预防、改善、和/或治疗由减少的睾丸酮引起的症状或疾病的睾丸酮增强剂的维生素K的用途。 15、根据上述条款14的用途，其中维生素K含量为按重量0.0001％-100％。 16、根据上述条款14的用途，其中上述维生素K是维生素K2。 17、根据上述条款14的用途，其中维生素K是甲萘醌类-4和/或甲萘醌类-7。 18、根据上述条款14的用途，其中症状和疾病是肌肉、认知功能、集中力、意欲、血管柔软性、脂质代谢、生殖功能、男性性功能、和排尿功能的退化。
序列表
<120>睾丸酮增长剂
<130>NF2004P
<150>JP2006-173455
<151>2006-06-23
<160>2
<170>PatentIn版本3.1
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<213>人工序列
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<223>正向引物典型模型
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Claims (6)
1.维生素K作为活性成分在制备睾丸酮增强剂中的用途。
2.根据权利要求1的用途，其中上述维生素K是维生素K2。
3.根据权利要求1的用途，其中上述维生素K是甲萘醌类-4和/或甲萘醌类-7。
4.含有作为活性成分的维生素K的睾丸酮增强剂在制备预防、改善和/或治疗由减少的睾丸酮引起的症状或疾病的药物中的用途。
5.根据权利要求4的用途，其中症状或疾病是生殖功能和男性性功能减退。
6.含有作为活性成分的维生素K的睾丸酮增强剂在制备补充剂、保健食品和功能性食品中的用途。
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| PCT/JP2007/060341 WO2007148494A1 (ja) | 2006-06-23 | 2007-05-21 | テストステロン増加剤 |
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| US6093421A (en) | 1999-08-31 | 2000-07-25 | Biotics Research Corporation | Maca and antler for augmenting testosterone levels |
| JP2001136959A (ja) | 1999-11-17 | 2001-05-22 | Hiroyuki Sumi | 枯草菌菌体および／またはその産生物を含む培養物、これに由来する水溶性ビタミンｋ誘導体、これらを含む医薬、食品および飼料ならびにこれらの製造方法 |
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| WO2003026649A1 (en) | 2001-09-27 | 2003-04-03 | Applied Research Systems Ars Holding N.V. | Methods of increasing endogenous testosterone levels |
| JP2005306754A (ja) | 2004-04-19 | 2005-11-04 | Ｔｏｗａ Ｃｏｒｐｏｒａｔｉｏｎ 株式会社 | テストステロン増加組成物、テストステロン増加食品、テストステロン増加皮膚外用およびテストステロン増加薬 |
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| Title |
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| H Shirakawa et al.Vitamin K deficiency reduces testosterone production in the testis through down-regulation of the Cyp11a a cholesterol side chain cleavage enzyme in rats.《Biochimica et Biophysica Acta》.2006,第1760卷(第10期),第1482-1488页. * |
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| CN101472574A (zh) | 2009-07-01 |
| KR20090023562A (ko) | 2009-03-05 |
| US20090209653A1 (en) | 2009-08-20 |
| EP2033634A1 (en) | 2009-03-11 |
| US20140228447A1 (en) | 2014-08-14 |
| US8686049B2 (en) | 2014-04-01 |
| JPWO2007148494A1 (ja) | 2009-11-19 |
| RU2008148542A (ru) | 2010-06-20 |
| RU2431475C2 (ru) | 2011-10-20 |
| EP2033634A4 (en) | 2010-12-22 |
| JP5110478B2 (ja) | 2012-12-26 |
| WO2007148494A1 (ja) | 2007-12-27 |
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