CN1233175A - 作为3－羟基－3－甲基戊二酰基CoA(HMG－CoA)还原酶抑制剂的橙皮苷和橙皮素 - Google Patents

作为3－羟基－3－甲基戊二酰基CoA(HMG－CoA)还原酶抑制剂的橙皮苷和橙皮素 Download PDF

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CN1233175A
CN1233175A CN97198803A CN97198803A CN1233175A CN 1233175 A CN1233175 A CN 1233175A CN 97198803 A CN97198803 A CN 97198803A CN 97198803 A CN97198803 A CN 97198803A CN 1233175 A CN1233175 A CN 1233175A
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hesperidin
hesperetin
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卜成海
孙光熙
郑泰淑
权柄穆
金永国
崔度一
金成郁
裴基焕
朴镛福
崔明淑
黄仁奎
文锡植
权容国
安贞娥
李恩淑
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Abstract

一种抑制哺乳动物的3－羟基－3－甲基戊二酰基CoA(HMG－CoA)还原酶活性的药物组合物,包括有效量的作为活性组分的橙皮苷或橙皮素和药物学上可接受的载体,以及抑制哺乳动物的3－羟基－3－甲基戊二酰基CoA(HMG－CoA)还原酶活性的食品或饮料组合物,包括有效量的橙皮苷或橙皮素。

Description

作为3-羟基-3-甲基戊二酰基CoA(HMG-CoA)还原酶抑制剂 的橙皮苷和橙皮素
发明领域
本发明涉及一种抑制哺乳动物的3-羟基-3-甲基戊二酰基CoA(HMG-CoA)还原酶活性的药物组合物，该组合物包括作为活性组分的有效量的橙皮苷或橙皮素以及药物上可接受的载体，此外，还涉及包括有效量的橙皮苷或橙皮素的抑制HMG-CoA还原酶活性的食品或饮料组合物。
发明背景
近年来，冠状心循环疾病，如动脉粥样硬化和血胆甾醇过多已上升成为死亡的主要原因。据报道，血浆中胆甾醇浓度的提高能引起脂肪、巨噬细胞和泡沫细胞沉积在血管上，这种沉积导致形成斑，继而导致动脉粥样硬化(Ross,R.,Nature,362,801-809(1993))。降低血浆中胆甾醇浓度的一种方法是营养疗法，减少撮入胆甾醇和脂肪。另一种方法是降低肝脏中胆甾醇的生物合成速率。据报道，血胆甾醇过多可以通过抑制HMG-CoA还原酶(它是合成羟基戊酸的媒介，生物合成甾醇或类异戊二烯的是中间体)来降低胆甾醇生物合成速度有效地治疗(Cardiovascular Pharmacology,William W.Parmley and Kanu ChatterjeeEd.,Wolfe Publishing,pages8.6-8.7,1994)。
因此，人们做了很多工作，主要是开发抑制HMG-CoA还原酶的药物；其结果是可以从市场上买到由Penicillium sp.和Aspergillus sp.衍生的各种化合物。特别是由美国Merck Co.开发的Lovastatin和Simvastatin以及日本Sankyo Co.开发的Pravastatin已经商业化(C.D.R.Dunn,Stroke:Trends,Treatment and Markets(中风：趋势、治疗和市场)，SCRIPT Report,PJB Publications Ltd.,1995)。然而，药物是非常昂贵的，长期服用会产生副作用，肝脏中肌酸激酶增加。所以，还需要开发一种便宜的无毒性HMG-CoA还原酶抑制剂。
橙皮苷和橙皮苷的糖苷配基、橙皮素是在柠檬、柚子、橘子和橙子(Citrus sinensis)中发现的类黄酮，它们具有如下结构(Horowitz,Gentili,Tetrahedron.19.773(1943))：
橙皮苷已用于防止和治疗大脑贫血、视网膜出血和表紫斑(pelioma)，但是没有报道过橙皮苷或橙皮素对HMG-CoA还原酶的抑制活性。
发明概述
本发明的一个目的是提供一种抑制哺乳动物的HMG-CoA还原酶活性的药物组合物。
本发明的另一目的是提供一种抑制哺乳动物的HMG-CoA还原酶活性的食品或饮料组合物。
在本发明的一方面，提供了一种抑制哺乳动物的3-羟基-3-甲基戊酰基CoA(HMG-CoA)还原酶活性的药物组合物，它包括作为活性组分的有效量的橙皮苷或橙皮素，以及药物上可接受的载体。发明详细描述
本发明提供一种抑制HMG-CoA还原酶活性的药物组合物，包括作为活性组分的橙皮苷或橙皮素，以及药物上可接受的赋形剂、载体和稀释剂。
橙皮苷和橙皮素可以从柑桔属的皮中提取，也可以按Zemplen,Bognar,Ber..75.1043(1943)和Seka,Prosche,Monatsh.,69,284(1936)上公开的方法合成。进一步说，橙皮素可以通过橙皮苷水解来制备。
橙皮苷或橙皮素在0.5mg/Kg体重/天或更高的剂量下对HMG-CoA还原酶具有抑制作用，随用量的增加抑制作用也升高。
此外，不管它们的潜在功效，在使用小鼠进行的试验中，橙皮苷和橙皮素表现出低的毒性或促有丝分裂性(mitogenicity)。具体地说，当小鼠口服1,000mg橙皮苷/Kg体重的剂量时，未表现出毒性，这一量相当于体重为50Kg的人口服50-100g橙皮苷/Kg体重。进一步说，橙皮苷和橙皮素对肝脏功能没有副作用。
药物制剂可以按任何常规方法通过组合物来制备。在制剂的制备过程中，活性组分优选与载体混合或用载体稀释，或包封在载体中，载体可以是胶囊、球囊(sachet)或其它容器的形式。当载体作为稀释剂时，可以是固体、半固体或液体材料，起活性组分载体(vehicle)、赋形剂或介质的作用。所以，制剂可以是药片、药丸、粉剂、球囊、酏剂、分散液、乳化液、溶液、糖浆、气溶胶、软或硬凝胶胶囊、无菌注射液、无菌包装粉末等。
合适的载体、赋形剂和稀释剂的例子乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯树胶、藻酸盐、凝胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酯镁和矿物油。此外，制剂中可以包括填料、抗絮凝剂、润滑剂、增湿剂、调味剂、乳化剂、防腐剂等。本发明的组合物可以通过任何本领域内已知的方法制成在哺乳动物施服用后提供快速、持久或缓释活性组分的形式。
本发明的药物制剂可以通过种种方式施用，包括口服、经皮、皮下、静脉和肌内引入。对于人，橙皮苷或橙皮素的日服用量典型地为0.5-300mg/Kg体重/天，优选5-30mg/Kg体重/天，可以一次服用，也可以分几次服用。然而，应当理解，活性组分的实际服用量应根据不同因素确定，包括要治疗的情况、所选择的给药途径、各个病人年龄、性别、体重，以及病人症状的严重程度；因此，上述剂量的不应以任何方式限制本发明。
此外，橙皮苷和橙皮素可以引入到食品或饮料中以抑制HMG-CoA还原酶的活性。因此，本发明还提供了一种抑制HMG-CoA还原酶活性的食品或饮料组合物，包括有效量的橙皮苷或橙皮素。
正如上面所述，橙皮苷或橙皮素可以作为有效的、无毒药剂使用，以抑制HMG-CoA还原酶的活性。
以下实施例用于进一步说明本发明，但不是限定本发明的范围。
另外，除特别声明外，在下面给出的百分数，对于固体混合物中的固体、液体中的液体、液体中的固体分别是以重量/重量，体积/体积，重量/体积为基础的，所有反应都在室温下进行。实施例1：给动物施用橙皮苷和橙皮素
体重为约90-110克的24只四周龄的Sprague-Dawley鼠(Taihanlaboratory animal center,Korea)平均随机分成三个食疗组。三组小鼠喂给不同的高胆甾醇食物，即AIN-76实验动物食物(ICN Biochemicals,Cleveland,OH,USA)，分别含有1％胆甾醇(对照组)，1％胆甾醇和0.1％橙皮苷(橙皮苷组)，1％胆甾醇和0.1％橙皮素(橙皮素组)。喂给三组小鼠的食物的组成列于表Ⅰ。
                               表Ⅰ
食谱组分   对照组  橙皮苷组  橙皮素组
酪蛋白     20     20     20
D,L-蛋氨酸     0.3     0.3     0.3
玉米淀粉     15     15     15
蔗糖     49    48.9    48.9
纤维素粉*1      5      5      5
矿物混合物*1     3.5     3.5     3.5
维生素混合物*1      1      1      1
柠檬酸胆碱     0.2     0.2     0.2
玉米油      5      5      5
胆甾醇      1      1      1
橙皮苷*2     0.1
橙皮素*2     0.1
总量     100    100     100
*1：从TEKLAD Premier Co.(Madison,WI,USA)购得*2：从Sigma Chemical Company(St.Louis,Mo,USA)购得
鼠按特定食物和水自由进食六周，每天记录撮取食量，每七天称重，然后记录分析。所有老鼠都表现出正常的生长速度，从食物撮取量和体重的增长上三个组中没有发现明显的差异。实施例2：确定血浆内的总胆甾醇、HDL-胆甾醇和中性脂的含量
给鼠施用橙皮苷或橙皮素对血浆中胆甾醇和中性脂含量的效果按以下方法确定。
从三个食疗组的鼠采取血样，使用含有硫酸葡萄糖酯的HDL-胆甾醇试剂(Sigma Chemical Co.,Cat.No.352-3)分离血浆HDL组分。总胆甾醇和HDL-胆甾醇浓度用Sigma Diagnostic Kit Cat.No.352-100(SigmaChemical Co.,USA)(Allain等，Clin.Chem.,20,470-475(1974))确定。中性脂的浓度用Sigma Diagnostic Kit Cat.No.339-50(Bucolo,G.and David,H.,Clin.Chem.,19,476-482(1973))确定。结果列于表Ⅱ，与对照组比较，喂给橙皮苷的一组鼠中总血浆胆甾醇浓度降低了11％，在喂给橙皮素的一组鼠中降低了15％。
                      表Ⅱ
Figure A9719880300081
*总-C：总胆甾醇*HDL-C:HDL-胆甾醇*TG：甘油三脂实施例3：橙皮苷和橙皮素在HMG-CoA还原酶抑制中的活性(步骤1)制备微粒体
为了确定喂给鼠的橙皮苷和橙皮素对HMG-CoA还原酶-肝脏中合成胆甾醇的调节酶-的活性影响，从肝脏组织中分离微粒体作为酶源。
首先，用断头法杀死三组老鼠，切下肝脏，立即放入冰-冷的均化介质中(50mM K2PO4(pH7.0),0.2M蔗糖，2mM二硫苏糖醇(DTT))。在均化介质(2ml介质/g肝脏)中，用Waring搅拌器搅拌15秒钟将肝脏均化(在Potter-Elvehjem型玻璃均化器中用马达驱动的四氟乙烯杵冲击三次)。均浆在15,000xg下离心10分钟，获得的上清液在100,000xg下离心75分钟，获得微粒体粒状沉淀，然后再分散到含有50mM EDTA的均化介质中，并在100,000xg下离心60分钟。含有微粒体的上清液作为酶源。(步骤2)HMG-CoA还原酶测定
按照Shapiro等人的方法用[14C]HMG-CoA确定HMG-CoA还原酶的活性(Biochemica et Biophysica Acta,370,369-377(1974))如下。
在步骤1中获得的含有微粒体的上清液中酶在37℃下活化30分钟。向反应管中加入20μl的HMG-CoA还原酶测定缓冲液(0.25M K2PO4(pH7.0),8.75mM EDTA,25mM DTT,0.45M KCl和0.25mg/ml BSA),5μl的50mM NADPH,5μl的[14C]HMG-CoA(0.05μCi/管，最终浓度为120μM)，以及10μl的活化微粒体酶(0.03-0.04mg)，混合物在37℃下培养30分钟。通过向该混合物中加入10μl的6M HCl，反应被终止，混合物在37℃培养15分钟，使产物(甲羟戊酸)完全内酯化。在10,000xg下离心1分钟除去沉淀，上清液涂布到硅胶60G TLC板上(Altech,Inc.,Newark,USA)，然后，用苯∶丙酮展开(1∶1,v/v)。用一次性盖板刮掉Rf值为0.65-0.75的区域，并用1450Microbeta液体闪烁计数器(Wallacoy,Finland)测定其放射性。以每分钟内每mg蛋白质合成3,5-二羟基-3-甲基戊酸的皮摩尔数(pmol/min/mg蛋白质)计算酶的活性。所得结果列于表Ⅲ。
                        表Ⅲ
       组    对比组   橙皮苷组   橙皮素组
 HMG-CoA还原酶活性(皮摩尔/min/mg蛋白质) 147+12.5 112.1+12.8 118.5+14.3
从表Ⅲ可以看出，对照组的鼠具有相对高的HMG-CoA还原酶的活性，而喂给橙皮苷组和橙皮素组的鼠中观察到的HMG-CoA还原酶的活性分别比对照组低24％和19％。实施例4：口服橙皮苷的毒性
7-8周龄的无特定病原体的ICR雌性小鼠(8只)，每只体重约25-29g，以及雄性小鼠(8只)，每只体重约34-38g，在22±1℃的温度、55±5％的湿度和12L/12D光周期下饲养，饲料(Cheiljedang Co.小鼠及大鼠饲料)和水经灭菌后喂给小鼠。
橙皮苷溶解在0.5％的吐温80中，其浓度为100mg/ml，小鼠口服该溶液，其量为0.2ml/20g小鼠体重。服用溶液后，对老鼠进行为期10天的观察，观察其副作用或死亡：服用后1、4、8、12小时观察一次，以后是每隔12小时观察一次。每天记录小鼠的体重变化以考察橙皮苷的作用。在第10天，杀掉小鼠以肉眼观察其内脏。
在第10天，所有的小鼠都存活，表明剂量为1,000mg/kg的橙皮苷对小鼠没有毒性。尸检表明，在10天的试验中，小鼠没有任何病理异常，体重也没有减少。因此，可以推断，口服橙皮苷对人体没有毒性。
以下配方实施例仅用于说明本发明，而不以任何方式限定本发明的范围。配方实施例
按以下配方制备硬凝胶胶囊：
                                        量(mg/胶囊)
活性组分(橙皮苷)                        20
淀粉，干                                160
硬脂酸镁                                20
总量                                    200mg
本发明已根据具体实施方案进行了描述，应当认识到，本领域内的技术人员可以作出各种改进和变化，但都在本发明的权利要求书限定的范围内。

Claims (6)

1．一种抑制哺乳动物的3-羟基-3-甲基戊二酰基CoA(HMG-CoA)还原酶活性的药物组合物，包括有效量的作为活性组分的橙皮苷或橙皮素和药物学上可接受的载体。
2．如权利要求1的组合物，其中，该哺乳动物是人类。
3．如权利要求2的药物组合物，其中，所述的有效量的橙皮苷为0.5-300mg/kg体重/天。
4．如权利要求2的药物组合物，其中，所述的有效量的橙皮素为0.5-300mg/kg体重/天。
5．一种抑制哺乳动物的3-羟基-3-甲基戊二酰基CoA(HMG-CoA)还原酶活性的食品组合物，包括有效量的橙皮苷或橙皮素。
6．一种抑制哺乳动物的3-羟基-3-甲基戊二酰基CoA(HMG-CoA)还原酶活性的饮料组合物，包括有效量的橙皮苷或橙皮素。
CN97198803A 1996-10-14 1997-10-13 作为3－羟基－3－甲基戊二酰基CoA(HMG－CoA)还原酶抑制剂的橙皮苷和橙皮素 Expired - Fee Related CN1104897C (zh)

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TWI634886B (zh) * 2014-08-22 2018-09-11 財團法人國防教育研究基金會 Compound composition for liver-free side effects with reduced liver fat for treating symptoms of non-alcoholic fatty liver disease (NAFLD)

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