CN103751174B - 五味子单体化合物在制备预防和治疗扑热息痛所致肝毒性药物中的应用 - Google Patents
五味子单体化合物在制备预防和治疗扑热息痛所致肝毒性药物中的应用 Download PDFInfo
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Abstract
本发明公开五味子单体化合物在制备预防和治疗APAP所致肝毒性药物中的应用,所述五味子单体化合物为五味子甲素、五味子丙素、五味子醇甲或五味子酯甲。通过实验发现所述五味子有关单体化合物能够显著降低APAP所致肝损伤模型动物的丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)含量,抑制肝细胞中还原性谷胱甘肽的消耗,并且有效改善肝细胞坏死程度,实验结果表明五味子单体化合物对APAP引起的肝毒性症状具有显著的治疗和保护效果。
Description
技术领域
本发明属于医药领域,具体涉及五味子单体化合物在制备预防和治疗扑热息痛所致肝毒性药物中的应用。
背景技术
五味子为木兰科多年生落叶藤本植物五味子成熟果实,分为北五味子Schisandrachinensis(Turcz.)baill和南五味子SchisandrasphenantheraRehd.etWils。五味子富含木脂素类、三萜类、倍半萜类、有机酸、挥发油和多糖等成分,其中木脂素类成分对人体多方面有益,其应用范围和开发前景越来越得到大家的关注。五味子作为中药功能益气生津、敛肺滋肾、止泻、涩精、安神,可治久咳虚喘、津少口干、遗精久泻、健忘失眠等症。现代药理研究还表明五味子具有良好的保护肝脏作用,其具体表现在①对化学物质所致肝毒性损伤的保护作用;②对脂质过氧化、促进肝再生的作用;③对肝脏蛋白质及肝糖原合成促进作用;④对细胞色素P450诱导,增加肝脏解毒功能的作用。
扑热息痛(对乙酰氨基酚,acetaminophen,APAP)是一种广泛应用的非处方解热镇痛药。治疗剂量的APAP疗效确切,治疗量的APAP用药安全,但是急性或蓄积性的过量会导致严重的肝损伤,甚至急性肝衰竭(Acuteliverfailure,ALF)。在美国、英国、澳大利亚及其它欧美国家,APAP过量是药物性肝损伤和ALF最常见的原因。而且APAP应用非常广泛消费量巨大,在我国如百服宁、白加黑、泰诺、999感冒灵、维c银翘片等日常用药均含有大量的APAP。在英国和美国每年因药物中毒而住院的患者中,由APAP所引起的分别占到50%和10%。由于APAP用药的普遍性和广泛性,APAP所致肝毒性一直受到广泛关注和重视。APAP过量服用时,大量的APAP由CYP450酶氧化形成N-乙酰对苯醌亚胺(NAPQI)。NAPQI导致谷胱甘肽(GSH)耗竭,并与细胞内蛋白特别是线粒体蛋白共价结合,引发线粒体氧化应激。通过氧化应激反应和活性氧簇(ROS)的生成,可激活c-Jun氨基末端激酶(JNK)的磷酸化和核转位,进一步促进和放大线粒体氧化应激,引发线粒体膜流动性降低、线粒体通透性转换孔(MPT)的开放,诱发线粒体功能异常,最终导致肝细胞的损伤、凋亡和坏死。
N-乙酰半胱氨酸(NAC)是目前临床上用于治疗APAP急性中毒的经典药物,但该药物的局限之处在于其治疗窗较窄,对APAP中毒急性后期的治疗无效,且长期给予高剂量NAC可干扰正常肝细胞线粒体代谢过程,阻断NF-kB信号通路从而抑制APAP肝损伤后的肝再生。
因此,有必要寻找和发现更多从不同机制治疗APAP所致肝损伤的药物的有效治疗药物。故而,针对预防或治疗扑热息痛肝毒性的药物研发越来越受到人们的重视,也是目前亟需的。
发明内容
本发明的发明目的在于提供五味子单体化合物在制备预防和治疗APAP所致肝毒性药物中的应用。
本发明的上述目的通过如下技术方案予以实现:
五味子单体化合物在制备预防和治疗APAP所致肝毒性药物中的应用。所述五味子单体化合物为五味子甲素、五味子丙素、五味子醇甲或五味子酯甲。
所述五味子单体化合物为五味子丙素。
本发明所述药物还包括医药领域常规的药物载体,如填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂,矫味剂、防腐剂等。
所述填充剂为淀粉、蔗糖、甘露醇或乳糖。
所述黏合剂为纤维素衍生物、藻酸盐、明胶、淀粉浆或聚乙烯吡咯烷酮。
所述湿润剂为甘油。
所述崩解剂为琼脂、碳酸钙或碳酸氢钠。
所述吸收促进剂为本领域公知的吸收促进剂,可选自季胺类化合物、脂肪酸及其混合物等。优选的,季胺类化合物为烷基二甲基苄基氯化铵或烷基二甲基乙基苄基氯化胺,脂肪酸为葵酸、油酸或其单甘油脂。
所述表面活性剂为滑石粉、硬脂酸镁或聚乙二醇。
所述矫味剂为糖精钠、蔗糖或甜蜜素。
所述防腐剂为苯甲酸、山梨酸或尼泊金。
本发明所述药物可以为医药领域常规剂型,包括胶囊剂、颗粒剂、片剂、散剂、溶液剂、乳剂、混悬剂等。
根据实际需要,所述药物的剂型还可以是缓释剂或控释剂。
现有技术虽然已经有相关五味子单体化合物用于降低抗癌药物引起的肝毒性等副作用,但是APAP引起的肝毒性症状与抗癌药物引起的肝毒性症状存在本质区别。有研究表明,APAP药物在生物转化过程中产生毒性较大的自由基代谢产物N-乙酰-对-苯醌亚胺(NAPQI),NAPQI会导致谷胱甘肽(GSH)耗竭,并与细胞内蛋白特别是线粒体蛋白共价结合,该产物与肝脏大分子不可逆共价结合,如服用中毒剂量,产生大量毒物,肝中GSH缺乏代谢物储积,从而引起细胞损害和肝坏死。而大部分抗癌药物本身毒性大,对正常细胞都有损伤作用,当其在肝脏聚集是会发生明显的毒副作用,引起肝损伤和坏死,表现出肝毒性症状。
正是存在上述区别,治疗和预防APAP引起肝毒性症状最好的途径是抑制GSH的消耗,而常规抗癌药物基本仅能通过控制剂量的摄入适当减缓毒副作用。通过大量实验,本发明发现五味子甲素、五味子丙素、五味子醇甲、五味子酯甲等五味子单体化合物可以降低扑热息痛所致肝损伤中的丙氨酸氨基转移酶和天冬氨酸氨基转移酶活性,提高线粒体内GSH水平,从而能够改善肝细胞坏死,起到预防和治疗APAP引起肝毒性症状。目前,本发明五味子单体化合物可以用于制备预防和治疗APAP引起肝毒性药物中的应用并未在现有技术中报道。
本发明具有如下有益效果:
本发明的实验以一次性过量给予APAP致小鼠急性肝损伤为模型,通过实验发现所述五味子有关单体化合物能够显著降低APAP所致肝损伤模型动物的丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)含量,抑制肝细胞中还原性谷胱甘肽的消耗,并且有效改善肝细胞坏死程度,实验结果表明五味子单体化合物对APAP引起的肝毒性症状具有显著的治疗和保护效果。
附图说明
图1为五味子甲素、五味子丙素、五味子醇甲、五味子酯甲对扑热息痛所致肝损伤小鼠程度结果图;
图2为五味子甲素、五味子丙素、五味子醇甲、五味子酯甲对扑热息痛所致肝损伤小鼠血清ALT、AST活性的影响结果图;
图3为五味子甲素、五味子丙素、五味子醇甲、五味子酯甲对扑热息痛所致肝损伤小鼠肝脏胞浆GSH,线粒体GSH的影响结果图;
图4为五味子单体对Nrf2相关通路mRNA表达量的影响结果图;
其中,A为空白对照组;B为扑热息痛造模组;C为五味子甲素给药造模组;D为五味子丙素给药造模组;E为五味子醇甲给药造模组;F为五味子酯甲给药造模组。
具体实施方式
下面结合具体实施例对本发明作进一步的解释说明,但具体实施例并不对本发明作任何限定。除非特别说明,实施例中所涉及的试剂、方法均为本领域常用的试剂和方法。
实施例1
一、实验材料
实验动物:C57BL/6小鼠,雄性,日龄35-42天,由中山大学(大学城)实验动物中心提供动物合格证号SCXK(粤)2011-0029.正常小鼠用维持饲料喂养。
药品和试剂:五味子甲素、五味子丙素、五味子醇甲、五味子酯甲(≥98%,上海融禾医药科技有限公司),扑热息痛(Sigma-AldrichCo.),还原型谷胱甘肽测定试剂盒(南京建成生物工程研究所)。
实验仪器:5417-R低温高速离心机(德国Eppendorf公司);多功能酶标仪(美国Moleculardevices公司);;梯度PCR仪(德国Eppendorf公司);7500RealTimePCRSystem(美国AppliedBiosystems公司)。
二、试验方法和给药方案
1.五味子单体化合物灌胃液的配制:用0.5%羧甲基纤维素钠配制0.025mmol/ml的五味子甲素、五味子丙素、五味子醇甲、五味子酯甲灌胃液(灌胃体积为0.1ml/10g,剂量为0.5mmol/kg/d)。
2.扑热息痛溶液的制备:取扑热息痛约0.8g,精密称定,加2N氢氧化钠溶液1.6ml后,加生理盐水至20ml,于温水浴中使其溶解,制成40mg/ml的小鼠肝损伤造模溶液(腹腔注射体积为0.1ml/10g,剂量分别400mg/kg),测定pH值(约10左右)。
3.小鼠随机分为8组,每组6只,小鼠每12小时灌胃一次,连续灌胃7次,第四天最后一次给药后15min腹腔注射APAP,小鼠于给予APAP溶液6h后,摘眼球取血然后处死,解剖取肝脏,部分肝脏置于10%甲醛中固定,剩余置-80℃冷冻保存。血液于3000×g离心10分钟得到血清,送中山大学实验动物中心检测生化指标。肝脏组织用于生化指标检测,提取RNA和蛋白及分子机制研究。
三、肝脏组织与血清生化指标检测
肝组织切片与H&E染色由中山大学实验动物中心病理切片室完成,小鼠肝脏解剖切片结果如图1所示。血清中的ALT,AST,利用美国BECKMANCX5全自动生化分析仪检测,肝脏中的GSH检测方法按照试剂盒的说明书来完成。小鼠血清ALT、AST活性检测结果如图2所示,肝脏总GSH和线粒体GSH检测结果如图3所示。
四、肝脏mRNA表达量检测
按照Trizol试剂的说明书得到小鼠肝细胞总RNA,按照RT试剂盒说明书得到cDNA,按照qRT-PCR试剂盒说明书检测特定基因的mRNA表达量。实验涉及的引物序列如表1所示。小鼠Nrf2相关通路mRNA表达量检测结果如图4所示。
表1.引物序列
Gene | Species | Forward primer (5′→3′) | Reverse primer (5′→3′) |
Gapdh | Mouse | AGGTCGGTGTGAACGGATTTG | GGGGTCGTTGATGGCAACA |
Ho-1 | Mouse | AAGCCGAGAATGCTGAGTTCA | GCCGTGTAGATATGGTACAAGGA |
Nqo1 | Mouse | AGGATGGGAGGTACTCGAATC | AGGCGTCCTTCCTTATATGCTA |
Gclc | Mouse | GGCTACTTCTGTACTAGGAGAGC | TGCCGGATGTTTCTTGTTAGAG |
Nrf2 | Mouse | CTTTAGTCAGCGACAGAAGGAC | AGGCATCTTGTTTGGGAATGTG |
五、数据统计
各组实验数据均以mean±S.E.M.表示,采用GraphPadPrism5软件进行统计分析,采用unpairedStudent’sttest进行两组间比较,P<0.05被认为有显著性差异。
六、实验结果
1、五味子单体减轻扑热息痛所致肝坏死程度
如图1所示,与空白对照组相比,扑热息痛造模组小鼠的肝脏解剖在体外观察发现明显的肝坏死病理改变,表现为中央静脉周边肝细胞水样变性(40-50%),少量肝细胞坏死(10-20%)。协同给予五味子酯甲中央静脉周边肝细胞水样变性下降,肝细胞未见坏死。协同给予五味子甲素和五味子醇甲与造模组比较肝细胞坏死下降。协同给予五味子丙素,肝脏形态趋于正常,肝板排列整齐,肝细胞未见水肿、变性或坏死改变,汇管区未见炎细胞浸润,肝窦未见扩张,枯否细胞未见增生,五味子丙素具有强烈的保护作用,优于其它单体化合物。
2、五味子单体对扑热息痛造模小鼠血清生化指标的改变
如图2所示,与空白对照组相比,扑热息痛造模组小鼠的ALT、AST水平分别上升至12540±2415和12940±3061U/L,提示扑热息痛能够造成严重的肝损伤。分别协同给予五味子甲素、五味子丙素、五味子醇甲以及五味子酯甲能显著下调血清中ALT,AST水平,其中ALT水平相对造模组下调31.6%、97.2%、73.5%和92.1%,AST水平相对造模组下调39.3%、95.2%、75.6%和88.7%,该结果提示五味子单体能够有效保护扑热息痛所致小鼠的肝损伤,其中五味子五味子丙素下调血清中ALT,AST达到97.2%和95.2%,作用效果优于其它单体化合物。
3、五味子单体上调肝细胞线粒体中GSH含量
如图3所示,扑热息痛造模组与空白组相比,肝脏线粒体GSH含量下降35.4%,说明给予扑热息痛在耗竭肝脏中GSH,而五味子丙素上调肝脏总GSH达到14.7%,具有预防整体肝脏GSH耗竭的作用,与造模组比较五味子甲素及五味子酯甲上调肝脏线粒体GSH含量1.55和1.57倍,趋于正常水平,提示五味子单体通过上调GSH水平减轻扑热息痛所致的肝损伤。
4、五味子单体对小鼠Nrf2及相关基因mRNA表达的影响
如图4所示,与扑热息痛造模组相比,协同给予五味子丙素的小鼠Nrf2mRNA表达水平上调,该结果提示五味子丙素能激活Nrf2,同时上调Nrf2的下游靶基因Gclc和Nqo1mRNA表达量。该结果提示五味子丙素预防与治疗扑热息痛所致肝损伤作用的机制可能涉及到Nrf2通路。
Claims (10)
1.五味子单体化合物在制备预防和治疗APAP所致肝毒性药物中的应用,其特征在于,所述五味子单体化合物为五味子丙素或五味子酯甲。
2.根据权利要求1所述应用,其特征在于,所述五味子单体化合物为五味子丙素。
3.根据权利要求1所述应用,其特征在于,所述药物还包括药物载体。
4.根据权利要求3所述应用,其特征在于,所述药物载体选自填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂,矫味剂或防腐剂中的一种或多种。
5.根据权利要求4所述应用,其特征在于,所述填充剂为淀粉、蔗糖、甘露醇或乳糖;所述粘合剂为藻酸盐、明胶、淀粉浆或聚乙烯吡咯烷酮。
6.根据权利要求4所述应用,其特征在于,所述湿润剂为甘油;崩解剂为琼脂、碳酸钙或碳酸氢钠。
7.根据权利要求4所述应用,其特征在于,所述吸收促进剂为季胺化合物或脂肪酸;所述表面活性剂为滑石粉、硬脂酸镁或聚乙二醇;所述矫味剂为糖精钠、蔗糖或甜蜜素。
8.根据权利要求4所述应用,其特征在于,所述防腐剂为苯甲酸、山梨酸或尼泊金。
9.根据权利要求1-8中任一项所述应用,其特征在于,所述药物的剂型包括胶囊剂、颗粒剂、片剂、散剂、溶液剂、乳剂、混悬剂。
10.根据权利要求1-8中任一项所述应用,其特征在于,所述药物的剂型包括缓释剂或控释剂。
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CN114948937B (zh) * | 2022-04-28 | 2023-09-15 | 浙江大学智能创新药物研究院 | 五味子丙素在制备治疗瑞戈非尼肝脏毒性药物中的应用 |
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Non-Patent Citations (5)
Title |
---|
五味子对扑热息痛肝脏毒性的保护作用;刘耕陶等;《药学学报》;19870930;第22卷(第9期);650-654 * |
五味子对扑热息痛致肝脏毒性的保护作用;李秀娟等;《齐齐哈尔医学院学报》;20010731;第22卷(第7期);727-728 * |
五味子研究进展评述;杨文胜等;《吉林林学院学报》;19930731;第9卷(第3期);第56-57页 * |
五味子药理作用研究进展;郭冷秋等;《中医药学报》;20060831;第34卷(第4期);51-53 * |
辽五味子综合开发与利用;于继鸿;《辽宁中医药大学学报》;20110831;第13卷(第8期);190-192 * |
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