CN106361739A - 共轭亚油酸或其衍生物在制备乙醛脱氢酶促进剂方面的应用 - Google Patents
共轭亚油酸或其衍生物在制备乙醛脱氢酶促进剂方面的应用 Download PDFInfo
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- CN106361739A CN106361739A CN201610749413.9A CN201610749413A CN106361739A CN 106361739 A CN106361739 A CN 106361739A CN 201610749413 A CN201610749413 A CN 201610749413A CN 106361739 A CN106361739 A CN 106361739A
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- linoleic acid
- conjugated linoleic
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- Life Sciences & Earth Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Enzymes And Modification Thereof (AREA)
Abstract
本发明属于生物医药领域,涉及共轭亚油酸或其衍生物在制备、乙醛脱氢酶活性促进剂、和减轻酒精肝损伤制剂方面的应用。本发明提供了共轭亚油酸或其衍生物(尤其是共轭亚油酸甘油酯)的新用途,经动物实验得到证实,具有提高肝脏乙醛脱氢酶和细胞色素P450 2E1的活性,并能够减轻酒精肝损伤肝脏病理的改变程度。
Description
技术领域
本发明属于生物医药领域,涉及共轭亚油酸或其衍生物在制备乙醛脱氢酶剂方面的应用。
背景技术
我国的酒文化有着悠久的历史,有无酒不成席之说。然而,酒精会对神经功能进行干扰,大量饮酒会导致醉酒。同时,由于酒精或其次级代谢产物在体内的蓄积,不仅导致醉酒不适症状的出现,引起肝毒性,甚至诱发肝癌。
酒精经胃肠道吸收进入血液,血液中酒精浓度反应了酒精的量,酒精经血液运送到肝脏代谢。酒精在体内代谢有两条途径,以乙醇脱氢酶和乙醛脱氢酶介导的零级经典途径和在酒精浓度过高时启动的以乙醇氧化酶系统(主要为P4502E1)和乙醛脱氢酶介导的一级代谢途径。酒精在乙醇脱氢酶、P4502E1作用下代谢为乙醛,然后在乙醛脱氢酶作用下代谢为乙酸,进入三羧酸循环,最终代谢为水和二氧化碳,因此乙醇脱氢酶、P4502E1和乙醛脱氢酶是酒精代谢过程中的关键性限速酶。一般人群中乙醇脱氢酶的活性是相当的,也就是说乙醇在吸收后能以较快的速度转化为乙醛;而乙醛脱氢酶的活性在人群中则存在较大的差异,乙醛脱氢酶基因突变会导致乙醛脱氢酶活性降低,乙醛脱氢酶突变基因的携带者对乙醛的分解能力下降,会导致乙醛在体内蓄积,出现明显的饮酒不适反应(典型表现为“亚裔脸红Asiaflush”、心跳加速和恶心等)。
乙醛脱氢酶基因突变主要分布在亚洲人群中,特别是东亚人群。在我国大陆地区,乙醛脱氢酶突变基因的分布也存在明显的地域差别,频率最高的是东南沿海地区,以福建为中心,往西北方向逐渐降低。因此相对很少出现乙醛脱氢酶突变基因的欧洲和非洲人群,亚洲人群更容易出现饮酒不适,酒精的肝毒性作用也更显著。
目前,乙醛脱氢酶难以获得,大多是从动物的肝脏、胰腺或肝细胞线粒体中提取,其资源有限且价格昂贵,因此很难大规模生产。因此,通过提高机体本身的乙醛脱氢酶的活性或含量来解酒具有重要意义。
然而,现有研究中,关于能提高乙醛脱氢酶活性的化合物或是制剂鲜有报道。中国专利CN201310549552.3公开了三唑类化合物可以作为制备乙醛脱氢酶2激活剂,该专利主要在体外实验中证明了三唑类化合物可以提高乙醛脱氢酶2激活剂,但在复杂的机体中,三唑类化合物促进乙醛脱氢酶2的活性的效果不得而知。此外,中国CN201310129281.6公开了alda-1也可用作乙醛脱氢酶的激活物,但其用于治疗脑组织神经病。因此,目前仍没有可以较好地应用于解酒领域中的乙醛脱氢酶促进剂。
共轭亚油酸是必需脂肪酸亚油酸的共轭双烯的多种位置与空间异构体的总称,由一系列共轭双键在C8和C10、C9和C11、C10和C11、C11和C13位置,具有位置和几何异构体的十八碳二烯酸构成。天然共轭亚油酸存在于反刍动物如牛、羊的乳脂及肉制品中,主要以c9,t11-CLA异构体形式存在。共轭亚油酸甘油酯、共轭亚油酸乙酯、共轭亚油酸钙盐等共轭亚油酸衍生物在小肠内水解为共轭亚油酸经肠粘膜细胞吸收,在肠粘膜细胞内重新合成为共轭亚油酸甘油脂,经淋巴系统进入血液循环,在体内发挥作用。因此无论是共轭亚油酸、共轭亚油酸甘油酯、共轭亚油酸乙酯或是共轭亚油酸钙盐,在体内均以相同的形式发挥功效。
已有研究表明,共轭亚油酸具有抗癌、减少体脂、降低血脂、减轻慢性炎症等多种生理活性作用。共轭亚油酸甘油酯是共轭亚油酸的天然存在形式。我国批准共轭亚油酸和共轭亚油酸甘油脂为新资源食品,可在普通食品中添加使用,此外共轭亚油酸甘油酯也作为保健食品,用于减肥、预防心血管疾病、糖尿病等。
虽然共轭油酸或其衍生物有多种保健功能,但此前,从未有人发现共轭亚油酸或其衍生物能够提高酒精代谢酶的活性,尤其是乙醛脱氢酶的活性。更无人将共轭亚油酸或其衍生物作为治疗酒精性肝损伤的制剂。
发明内容
本发明目的在于提供了共轭亚油酸或其衍生物在制备乙醛脱氢酶活性/含量促进剂方面的应用。
本发明的另一目的还在于提供一种治疗酒精性肝损伤,尤其是急性酒精性肝损伤的制剂。
发明人在研究中发现,共轭亚油酸或其衍生物能够提高乙醛脱氢酶含量,从而加快酒精的代谢。
进入体内的乙醇绝大部分在肝脏通过两条独立的代谢途径进行代谢。一条是乙醇脱氢酶(ADH)途径,该途径存在于肝细胞质液中,在ADH的催化下,以NAD+作辅助因子,将乙醇氧化为乙醛,生成的乙醛在乙醛脱氢酶(ALDH)作用下转变为无害的乙酸。另一条是微粒体乙醇氧化系统(MEOS)途径,该系统存在于肝微粒体内,当肝组织中乙醇浓度超过10mmol/L时或长期饮酒精群体性中,MEOS途径被激活,成为乙醇的主要代谢途径。
在酒精的代谢过程中,乙醛脱氢酶是酒精代谢的限速酶。无论是ADH途径还是MEOS途径,乙醛脱氢酶均起关键性作用。对于亚裔人种,乙醛脱氢酶尤为重要。这是因为,亚裔人种有一半以上的人口乙醛脱氢酶基因2(ALDH2)发生突变,导致乙醛脱氢酶活性低,无法进行正常而高效的酒精代谢。提高体内乙醛脱氢酶的活性或含量对于酒精代谢有重要意义。然而,目前仍没有可以较好地应用于解酒领域中的乙醛脱氢酶促进剂。本研究首先发现了共轭亚油酸或其衍生物能够提高乙醛脱氢酶的活性。
在本发明的动物实验中,施用共轭亚油酸或其衍生物的实验组,肝脏中ALDH的含量相对于阳性组和对照组均有显著提高。更为突出的是,实验组的中的低剂量具有更显著的效果。低剂量的实验组ALDH含量相对于未施用的对照组提高32.7%(P<0.001)。
在MEOS途径中,需要细胞色素P450的存在和烟酰胺腺嘌呤磷酸二核苷酸(NADPH)的参与。MEOS有多种细胞色素P450s组成。其中CYP2E1对乙醇代谢Km值较低,且能被酒精诱导,是MEOS乙醇代谢途径的关键酶,在非乙醇脱氢酶氧化途径中起重要作用。
共轭亚油酸或其衍生物除了能够提高体内乙醛脱氢酶的含量,还能够提高细胞色素P450 2E1(CYP2E1)含量有所升高,在体内酒精浓度过高时,加快酒精的代谢。
在本发明的动物实验中,共轭亚油酸或其衍生物可使醉酒模型的细胞色素P4502E1(CYP2E1)含量有所升高,且低剂量组与对照组相比差异有显著性意义;而阳性药对CYP2E1含量均无明显作用。
事实上,单纯的细胞色素P450 2E1(CYP2E1)增加可起肝损伤。如乙醇诱导CYP2E1的基因和蛋白表达增加.使反应性氧增多、自由基生成增加.进一步促进脂质过氧化反应。使丙二醛(MDA)生成增加,消耗还原型谷胱甘肽(GSH),生成大量过氧化脂质,抑制抗氧化系统的保护作用,使体内氧化–抗氧化制失衡,引发肝损害。
而发明人发现,在使用共轭亚油酸或其衍生物的实验组中,MDA不但没有增加,反而降低了。MDA是生物体内脂质过氧化物的最终代谢产物,它的降低预示着生物体内过氧化物的减少。在本发明的动物实验中,实验组和阳性组均可以降低肝脏中的MDA,尤其是实验组中的GLA-TG高剂量组。由此可见共轭亚油酸或其衍生物可以通过一定的抗氧化作用发挥护肝解酒的功能。
本发明的共轭亚油酸或其衍生物适用的对象为酒精摄入者。尤其是大量饮酒对象。因为共轭亚油酸甘油酯或其衍生物不仅可以加快ADH途径,同时能加快MOES途径。
此外,本发明的共轭亚油酸甘油酯或其衍生物适用于携带ALDH突变基因的人群,如饮酒后容易出现“亚裔脸红”的亚裔人种。亚裔人种有一半以上的人口的ALDH基因发生突变,ALDH的活性较低。本发明尤其适用的群体为亚裔人种中ALDH基因发生突变的群体。
饮酒后容易出现脸红、恶心、心跳加速、头痛等不适反应人群,在饮酒前、饮酒过程、或饮酒后摄入共轭亚油酸或其衍生物,或者含有共轭亚油酸或其衍生物的混合制剂。这样能够帮助这些人群快速将酒精代谢排出体外,以减轻饮酒不适和保护其肝脏功能。
本发明中所述的共轭亚油酸衍生物选自共轭亚油酸甘油酯、共轭亚油酸乙酯、共轭亚油酸钙盐中的一种或几种组合。
优选地,所述的衍生物为共轭亚油酸甘油酯。
所述的共轭亚油酸或其衍生物用于乙醛脱氢酶活性促进剂的剂量不少于0.01g/kg体重;优选0.02~0.12g/kg体重;更优选0.04~0.08g/kg体重。
本发明还发现共轭亚油酸甘油酯或其衍生物对酒精肝损伤具有一定的减轻作用。
具体地,本发明利用小鼠急性酒精性肝损伤模型,通过肝功和肝脏病理检测评价共轭亚油酸或其衍生物对小鼠急性酒精性肝损伤的作用。在连续10天灌胃给予白酒后,实验组的肝细胞水肿、脂肪变性等病理改变较阳性组和对照组均出现较少。同时,实验组(受试品CLA-TG)相对于阳性组和模型组,显著降低总胆红素(TBil)含量,维持在正常组水平(TBil含量增加表示有肝有损伤)。
表明共轭亚油酸或其衍生物对酒精性肝损伤小鼠有一定的治疗作用,尤其是急性酒精肝损伤。
本发明中所述的共轭亚油酸衍生物选自共轭亚油酸甘油酯、共轭亚油酸乙酯、共轭亚油酸钙盐中的一种或几种组合。
优选地,所述的衍生物为共轭亚油酸甘油酯。
本发明中的所述的阳性组为施用海王金樽组,所述的海王金樽已被证实可以改善醉酒状态,降低醉酒程度,减轻酒精对身体的损害及因醉酒引发的各种症状,消除头痛、乏力、倦怠、食欲不振等酒后不适;并改善酒精所致的机体血液微循环障碍,使人体内各组织器官的代谢、生理功能得以正常运行。
本发明提供了一种减轻/治疗酒精性肝损伤,尤其是极性酒精肝损伤的制剂,所述的解酒制剂含有共轭亚油酸或其衍生物。
所述的制剂还可以明显减轻急性酒精中毒引起的肝脏病理改变。
所述的肝脏病理改变例如但不限于:肝细胞水肿、轻度肝细胞脂肪变性、条带状肝细胞嗜酸性变或肝细胞炎细胞浸润。
所述的制剂用于减轻/治疗酒精性肝损伤的剂量不少于0.01g/kg体重;优选0.02~0.12g/kg体重;更优选0.04~0.08g/kg体重。
本发明首次发现了共轭亚油酸或其衍生物可以提高乙醛脱氢酶的活性从而促进酒精的代谢。这对于乙醛脱氢酶突变的亚裔人种具有十分重要的意义。同时,本发明还发现了共轭亚油酸或其衍生物具有护肝功效,对酒精性肝损伤有一定的减轻/治疗作用。
附图说明
图1.CLA-TG对醉酒模型小鼠丙二醛(MDA)含量的作用(X±SD.)与对照组比较,*P<0.05
图2.CLA-TG对醉酒模型小鼠乙醛脱氢酶(ALDH)含量的作用(X±SD.)与对照组比较,**P<0.01
图3.CLA-TG对醉酒模型小鼠细胞色素P450 2E1(CYP2E1)含量的作用(X±SD.)与对照组比较,***P<0.001
图4.CLA-TG对急性酒精性肝损伤模型小鼠谷草转氨酶(AST)活性的作用(X±SD.)与正常组比较,▲P<0.05
图5.CLA-TG对急性酒精性肝损伤模型小鼠总胆红素(Tbil)含量的作用(X±SD.)
图6.各组小鼠肝脏显微照片图(HE,×100)A:正常对照组;B:酒精性肝损伤模型组;C:阳性组;D:CLA-TG低剂量组;E:CLA-TG中剂量组;F:CLA-TG高剂量组。
具体实施方式
以下通过具体的实施例进一步说明本发明的技术方案,具体实施例不代表对本发明保护范围的限制。其他人根据本发明理念所做出的一些非本质的修改和调整仍属于本发明的保护范围。
1、实验动物:KM小鼠,18g-20g,SPF级,来源于北京华阜康生物科技股份有限公司,实验动物质量合格证号:SCXK(京)2014-0004。
2、动物饲养条件:SPF级动物屏障环境中饲养,12只/笼,自由摄取常规固体饲料及纯净水,动物设施许可证:SYXK(京)2013-0023。
3、试剂及耗材
3.1受试物
共轭亚油酸甘油酯(CLA-TG),由大连槿藏商贸有限公司提供,批号:R1407062,密封冰箱冷藏保存。
3.2阳性药
海王牌金樽片,由深圳市海王健康发展有限公司生产,批号:20150102,规格:1g*3片*6袋。
3.3其他试剂即耗材
白酒:红星牌二锅头白酒,由北京红星股份有限公司生产,酒精含量56%(V/V),生产批号:20150328;氯化钠(NaCl),分析纯,500g装,国药集团化学试剂有限公司,批号:20140529;三氯乙酸,分析纯,北京化学试剂公司,500g装,批号:041012;盐酸(HCl),分析纯,北京化工厂,500ml装,批号:20010538;TBA(硫代巴比妥酸),25g装,国药集团化学试剂有限公司,批号:YF20060608;羧甲基纤维素钠(CMC),批号:040706,厂商:广东汕头市西陇化工厂。
蛋白定量测试盒(考马斯亮蓝法),货号:A045-2,生产批号:20151216,有效期:20160615;谷胱甘肽-S转移酶(glutathione S-transferase,GST)测定试剂盒,货号:A004,生产批号:20151226,有效期:20160625。以上试剂盒均来源于南京建成生物工程研究所。
小鼠乙醛脱氢酶(aldehyde dehydrogenase,ALDH)酶联免疫分析试剂盒,有效期:201606,LOT:201512,REF:SBJ-MO692;小鼠细胞色素P450家族成员2E1(cytochrome P4502E1,CYP2E1)酶联免疫分析试剂盒,有效期:201606,LOT:201512,REF:SBJ-MO693。以上试剂盒由森贝伽(南京)生物科技有限公司提供。
谷丙转氨酶(ALT)测定试剂盒,有效期:20170101,LOT:AUZ2678;谷草转氨酶(AST)测定试剂盒,有效期:20170101,LOT:AUZ2686;总胆红素(TBil)测定试剂盒,有效期:20160401,LOT:AUZ2724。以上试剂盒均由贝克曼库尔特实验系统(苏州)有限公司提供。
3.4仪器
IKA VORTEX1涡旋器:艾卡(广州)仪器设备有限公司(IKA中国);
F6/10型FLUKO超细匀浆器:上海弗克流体机械制造有限公司;
HERAEUS Labofuge400R型低温离心机:HERAEUS;
TGL-160aR型高速低温离心机:上海安亭科学仪器厂;
BIO-RAD MQX200型微孔板扫描酶标仪:美国Bio-RAD。
AU480全自动生化分析系统:贝克曼库尔特商贸(中国)有限公司。
实施例1CLA-TG对醉酒模型小鼠的解酒作用机制研究
实验步骤:
SPF级KM小鼠,♂,体重18-22g。小鼠60只,按体重随机分成5组,分别为:对照组、阳性组(海王金樽3g/kg)及CLA-TG高(3g/kg)、中(2g/kg)、低(1g/kg)剂量组。每组12只,阳性组小鼠灌胃给予(ig.)0.2ml/10g体重15%的海王金樽溶液,CLA-TG高、中、低剂量组小鼠分别ig.0.2ml/10g体重浓度为15%、10%、5%的CLA-TG溶液(用5%CMC助溶),模型组小鼠ig.等量CMC溶液,每天1次,连续3天。行为学观察实验前禁食一夜(12h)。实验当天给药30min后,各组小鼠均ig.0.165mL/10g白酒,造模后7h统一处死取肝脏,-80℃保存待用。冻存的小鼠肝脏制备10%肝匀浆后3000rpm离心取上清进行以下指标的检测。酶法测定小鼠肝脏乙醇脱氢酶(ADH)、谷胱甘肽转移酶(GST)活性及丙二醛(MDA)含量;ELISA法测定小鼠肝脏乙醛脱氢酶(ALDH)、细胞色素P450 2E1(CYP2E1)含量。
酶法测定及ELISA法测定参见《药理实验方法学》第4版相应章节。
实验结果:
CLA-TG对小鼠肝脏谷胱甘肽转移酶(GST)活性及丙二醛(MDA)含量的影响(表1和图1)。
小鼠肝脏谷胱甘肽转移酶(GST)活性和丙二醛(MDA)含量的测定结果显示,受试品CLA-TG和阳性药海王金樽对醉酒模型小鼠肝脏GST活性均无明显作用,但可使肝脏MDA含量有所减少,且CLA-TG高剂量组与对照组的差异有显著性意义。
进入体内的酒精或其代谢产物可产生大量的自由基导致肝细胞膜的脂质过氧化,因此具有抗氧化作用的物质能减轻酒精对肝组织的损害,从而加速乙醇的消除。丙二醛(MDA)是生物体内脂质过氧化物的最终代谢产物,它的降低预示着生物体内过氧化物的减少。我们的实验结果显示CLA-TG可明显减少醉酒模型小鼠肝脏中MDA的含量,表明CLA-TG可通过一定的抗氧化作用发挥护肝解酒的功能。
表1CLA-TG对小鼠肝脏GST和MDA的作用(X±SD.)
与对照组比较,*P<0.05
CLA-TG对小鼠肝脏乙醛脱氢酶(ALDH)、细胞色素P4502E1(CYP2E1)含量的影响(表2和图2-3)。
从表2可看出,受试品CLA-TG可使醉酒模型小鼠乙醛脱氢酶(ALDH)、细胞色素P4502E1(CYP2E1)含量有所升高,且低剂量组与对照组相比差异有显著性意义;而阳性药海王金樽对ALDH和CYP2E1含量均无明显作用。
表2CLA-TG对小鼠肝脏ALDH和CYP2E1的作用(X±SD.)
与对照组比较,**P<0.01,***P<0.001
进入体内的乙醇绝大部分在肝脏通过两条独立的代谢途径氧化为乙醛进行代谢。一条是乙醇脱氢酶(ADH)途径,该途径存在于肝细胞质液中,在ADH的催化下,以NAD+作辅助因子,将乙醇氧化为乙醛,生成的乙醛作为底物进一步在乙醛脱氢酶(ALDH)催化下转变为无害的乙酸。另一条是微粒体乙醇氧化系统(MEOS)途径,该系统存在于肝微粒体内,需要细胞色素P450的存在和烟酰胺腺嘌呤磷酸二核苷酸(NADPH)的参与。本实验结果显示CLA-TG可升高醉酒模型小鼠乙醛脱氢酶(ALDH)、细胞色素P4502E1(CYP2E1)含量,表明CLA-TG可通过增强肝脏MEOS和ALDH的活性来促进乙醇的氧化分解代谢,从而发挥其解酒作用。
共轭亚油酸甘油酯(CLA-TG)可通过增强肝脏微粒体乙醇氧化酶和乙醛脱氢酶的活性来促进乙醇的氧化分解代谢,并具有一定的抗氧化作用,从而发挥护肝解酒功能。
实施列2CLA-TG对小鼠酒精性肝损伤的作用研究
实验步骤:
SPF级ICR小鼠,♂,体重18-22g,72只。按体重随机分成6组,分别为:正常对照组、模型对照组、阳性组(海王金樽3g/kg)及CLA-TG高(3g/kg)、中(2g/kg)、低(1g/kg)剂量组,每组12只。阳性组小鼠灌胃给予(ig.)0.2ml/10g体重15%的海王金樽溶液,CLA-TG高、中、低剂量组小鼠分别ig.0.2ml/10g体重浓度为15%、10%、5%的CLA-TG溶液(用5%CMC助溶),正常组和模型组灌胃等量的纯水。灌胃后1h,模型组和各给药组用56度白酒(10ml/kg)灌胃进行造模建立急性酒精性肝损伤模型。连续10天。每天观察小鼠状态,每周称重。各组小鼠末次灌胃后,禁食不禁水12h,取血制备血清测定血清谷丙转氨酶(ALT)、谷草转氨酶(AST)活性和总胆红素(Tbil)含量;处死小鼠后剖取肝组织,称重计算肝脏指数,用10%多聚甲醛固定肝左大叶,石蜡包埋,切片,常规苏木精-伊红(HE)染色,镜检观察肝组织病理改变。
实验结果:
CLA-TG对小鼠体重和肝脏指数的影响
连续10天造模后,模型组小鼠的体重与正常组小鼠相比有明显的降低;肝脏系数有所增高,但差异无显著性意义。受试药CLA-TG和阳性药海王金樽对造模小鼠的体重和肝脏系数均无明显的影响(表3)。
表3CLA-TG对小鼠体重和肝脏指数的影响(X±SD.)
与正常组比较,▲▲P<0.01
CLA-TG对小鼠血清谷丙转氨酶(ALT)、谷草转氨酶(AST)活性和总胆红素(Tbil)含量的影响见表4和图4-5。
连续10天灌胃给予白酒后,模型组小鼠的血清ALT、AST活性与正常组小鼠相比均明显升高。从表4可看出,受试品CLA-TG和阳性药对血清ALT和AST活性均无明显的降低作用,相反CLA-TG高剂量还可明显升高血清ALT活性。实验组(受试品CLA-TG)相对于阳性组和模型组,显著降低TBil含量,维持在正常组水平(TBil含量增加表示有肝有损伤)。
表4CLA-TG对小鼠肝脏ALT、AST和TBil的作用(X±SD.)
与正常组比较,▲P<0.05,▲▲▲P<0.001;与模型组比较,***P<0.001
CLA-TG对小鼠酒精性肝损伤模型肝脏病变的治疗作用
(1)正常组:肝脏未见明显病理改变。
(2)酒精性肝损伤模型组:2例(2/12)轻度肝细胞水肿;1例(1/12)轻度肝细胞脂肪变性,条带状肝细胞嗜酸性变伴以炎细胞浸润;2例(1/12)部分肝细胞嗜酸性变。
(3)阳性组:1例(1/12)轻度肝细胞脂肪变性;1例(1/12)肝脏内小灶性炎细胞浸润。
(4)CLA-TG低剂量组:1例(1/12)轻度肝细胞脂肪变性;1例(1/12)中央静脉周围轻度肝细胞水肿。
(5)CLA-TG中剂量组:1例(1/12)轻度肝细胞脂肪变性。
(6)CLA-TG高剂量组:2例(2/12)肝脏内小灶性炎细胞浸润。其余肝脏未见明显病理改变。
镜检观察结果(图6)
(1)正常组(表5.1)
肝脏:肝小叶结构清晰,汇管区未见纤维组织增生及炎细胞浸润。
(2)酒精性肝损伤模型组(表5.2)
肝脏:2例轻度肝细胞水肿。1例轻度肝细胞脂肪变性,条带状肝细胞嗜酸性变,细胞体积缩小,胞浆嗜酸性增强,核浓缩,伴炎细胞浸润。2例部分肝细胞嗜酸性变。其余动物肝脏肝小叶结构清晰,汇管区未见纤维组织增生及炎细胞浸润。
(3)阳性组(表5.3)
肝脏:1例轻度肝细胞脂肪变性;1例肝脏内小灶性炎细胞浸润。其余动物肝小叶结构清晰,汇管区未见纤维组织增生及炎细胞浸润。
(4)CLA-TG低剂量组(表5.4)
肝脏:1例轻度肝细胞脂肪变性。1例中央静脉周围轻度肝细胞水肿。其余动物肝小叶结构清晰,汇管区未见纤维组织增生及炎细胞浸润。
(5)CLA-TG中剂量组(表5.5)
肝脏:1例轻度肝细胞脂肪变性。其余动物肝小叶结构清晰,汇管区未见纤维组织增生及炎细胞浸润。
(6)CLA-TG高剂量组(表5.6)
肝脏:2例肝脏内小灶性炎细胞浸润。其余动物肝小叶结构清晰,汇管区未见纤维组织增生及炎细胞浸润。
表5.1正常组肝脏病理改变
表5.2酒精性肝损伤模型组肝脏病理改变
表5.3阳性组肝脏病理改变
表5.4CLA-TG低剂量组肝脏病理改变
表5.5CLA-TG中剂量组肝脏病理改变
表5.6CLA-TG高剂量组肝脏病理改变
注:—未见病变+轻度病变++中度病变+++重度病变
肝脏病变分级标准:
轻度病变:病变范围小于肝小叶1/3。
中度病变:病变范围约占肝小叶1/3~2/3。
重度病变:病变范围大于肝小叶2/3。
连续10天灌胃给予白酒后,模型组小鼠的血清谷丙转氨酶(ALT)、谷草转氨酶(AST)活性与正常组小鼠相比均明显升高;并有部分小鼠出现轻度肝细胞水肿、轻度肝细胞脂肪变性、条带状肝细胞嗜酸性变或肝细胞炎细胞浸润等病理改变。表明本次实验建立的急性酒精性肝损伤小鼠模型的特征主要是血清ALT和AST活性的升高,并有一定程度的肝脏病理改变。受试品共轭亚油酸甘油酯(CLA-TG)对血清ALT和AST活性均无明显的降低作用,但可明显改善造模小鼠的肝细胞水肿、脂肪变性等病理改变,减少出现明显肝脏病理改变的小鼠例数。由此可见共轭亚油酸甘油酯(CLA-TG)对急性酒精性肝损伤小鼠有一定的治疗作用。
Claims (10)
1.共轭亚油酸或其衍生物在制备乙醛脱氢酶促进剂方面的应用。
2.如权利要求1所述的应用,其特征在于所述的乙醛脱氢酶促进剂能提高机体中乙醛脱氢酶的活性/含量。
3.如权利要求1所述的应用,其特征在于适用的对象为酒精摄入者;优选地,为亚裔人种;或者优选地,为乙醛脱氢酶突变者。
4.如权利要求1-3任一所述的应用,其特征在于所述的衍生物选自共轭亚油酸甘油酯、共轭亚油酸乙酯、共轭亚油酸钙盐中的一种或几种组合。
5.如权利要求1-3任一所述的应用,其特征在于所述的衍生物选自共轭亚油酸甘油酯。
6.如权利要求1-3任一所述的应用,其特征在于所述的共轭亚油酸或其衍生物用于乙醛脱氢酶活性促进剂的剂量不少于0.01g/kg体重;优选0.02~0.12g/kg体重;更优选0.04~0.08g/kg体重。
7.一种减轻/治疗酒精性肝损伤的制剂,其特征在于含有共轭亚油酸或其衍生物;优选地,所述的制剂适用人群为乙醛脱氢酶突变者;或者,为亚裔人种;更优选地,适用人群为东亚人种。
8.如权利要求7所述的制剂,其特征在于所述的衍生物选自共轭亚油酸甘油酯、共轭亚油酸乙酯、共轭亚油酸钙盐中的一种或几种组合。
9.如权利要求7所述的制剂,其特征在于所述的衍生物选自共轭亚油酸甘油酯。
10.如权利要求7所述的制剂,其特征在于用于减轻/治疗酒精性肝损伤的剂量不少于0.01g/kg体重;优选0.02~0.12g/kg体重;更优选0.04~0.08g/kg体重。
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