CN103599108B - 齐墩果酸在制备预防和治疗胆汁淤积症药物中的应用 - Google Patents
齐墩果酸在制备预防和治疗胆汁淤积症药物中的应用 Download PDFInfo
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- CN103599108B CN103599108B CN201310585202.2A CN201310585202A CN103599108B CN 103599108 B CN103599108 B CN 103599108B CN 201310585202 A CN201310585202 A CN 201310585202A CN 103599108 B CN103599108 B CN 103599108B
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- Medicinal Preparation (AREA)
Abstract
本发明公开齐墩果酸在制备预防和治疗胆汁淤积症药物中的应用。通过实验以过量给予石胆酸造成小鼠肝损伤为模型,协同给予齐墩果酸5~20 mg/kg后,能有效减轻肝损伤和降低胆汁酸水平,具体表现为小鼠存活率显著升高,血清中ALT,AST和ALP的活性显著降低,肝组织坏死程度显著减轻,同时血清中的总胆汁酸与总胆红素含量,以及肝脏中的总胆汁酸含量也有显著的降低。肝脏基因与蛋白表达分析证实齐墩果酸能够显著上调Mrp2,Mrp3,Mrp4表达,并且激活Nrf2,但对其它的胆汁酸转运体和代谢酶无显著影响。结果表明齐墩果酸能够预防治疗石胆酸所诱导的胆汁淤积性肝损伤,机制涉及Nrf2‑Mrps通路。
Description
技术领域
本发明属于医药领域,具体涉及齐墩果酸在制备预防和治疗胆汁淤积症药物中的应用。
背景技术
胆汁淤积是一种体内循环或者肝脏滞留过多的毒性胆汁酸而产生肝损伤的临床症状,最终可能发展成为致命性的肝疾病,例如原发性胆汁性肝硬化和硬化性胆管炎等。胆汁淤积的形成可能由于肝细胞胆汁分泌紊乱或者胆管阻塞造成。石胆酸(LCA)是一种毒性较强的疏水性次级胆汁酸,是由肠道细菌将鹅去氧胆酸(CDCA)的7α位去羟基化后生成。在慢性胆汁淤积性疾病患者的血中可检测到LCA水平的显著增加,并且研究发现在患者体循环中累积的LCA被认为能导致肝损害。此外,在动物水平上,给予小鼠过量的LCA能造成胆管部分梗阻以及胆管炎。因此,LCA作为一种胆汁淤积的造模药物广泛用于胆汁淤积治疗药物的研发中。
齐墩果酸作为一个五环三萜类的化合物广泛存在于一些药用植物中,在我国齐墩果酸已经成为OTC药物被用于治疗急慢性肝炎。国内外对齐墩果酸药理作用的报道主要有抗炎,糖尿病治疗以及抗肿瘤等,此外齐墩果酸被报道具有显著的肝保护作用,能够用于多种肝毒性药物如对乙酰氨基酚,四氯化碳等所致肝损伤的保护与治疗。最近有报道齐墩果酸能够导致小鼠的胆汁淤积,所用剂量高达90 mg/kg或以上,机制为影响调控胆汁酸稳态的基因表达,但并无特定指出齐墩果酸具体是通过影响哪些基因的表达来导致胆汁淤积,同时导致胆汁淤积的剂量高于齐墩果酸以往报道的肝保护剂量4倍左右。在低剂量下,齐墩果酸能否预防治疗胆汁淤积尚未有报道,本发明旨在通过动物实验揭示齐墩果酸能否在低剂量下预防和治疗LCA所诱导的小鼠胆汁淤积症,并探讨其内在机制。
发明内容
本发明的发明目的在于提供齐墩果酸在制备预防和治疗胆汁淤积症药物中的应用。
本发明的上述目的通过如下技术方案予以实现:
齐墩果酸在制备预防和治疗胆汁淤积症药物中的应用。
本发明所述药物还包括赋形剂和助剂等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。
所述填充剂可选自淀粉、蔗糖、甘露醇或乳糖。
所述黏合剂可选自纤维素衍生物、藻酸盐、明胶、淀粉浆或聚乙烯吡咯烷酮。
所述湿润剂可选自甘油。
所述崩解剂可选自琼脂、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。
所述表面活性剂可选自滑石粉、硬脂酸镁或钙和聚乙二醇。
所述矫味剂可选自糖精钠、蔗糖或甜蜜素。
所述防腐剂可选自苯甲酸、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。
本发明将齐墩果酸用于制备预防和治疗胆汁淤积症药物,预防和治疗胆汁淤积症是指通过激动Nrf2,上调胆汁酸外排转运体Mrp2,
Mrp3, Mrp4的表达,从而增加胆汁酸的外排来实现的,而不是通过降低胆汁酸摄入转运体Oatp1b2和Ntcp基因表达、增加胆汁酸外排转运体Bsep基因表达、增加胆固醇外排转运体Mdr3基因表达、增加胆汁酸代谢相关酶Cyp3a11,
Cyp2b10, Cyp7a1, Sult2a1和Ugt1a1基因表达、以及增加胆汁酸稳态相关核受体Pxr, Car和Fxr基因表达来实现的。
本发明具有如下有益效果:
本发明实验以过量给予石胆酸造成小鼠肝损伤为模型,协同给予齐墩果酸5, 10, 20 mg/kg后,能有效减轻肝损伤和降低胆汁酸水平,具体表现为小鼠存活率显著升高,血清中ALT,AST和ALP的活性显著降低,肝组织坏死程度显著减轻,同时血清中的总胆汁酸与总胆红素含量,以及肝脏中的总胆汁酸含量也有显著的降低,结果表明齐墩果酸能够预防治疗石胆酸所诱导的胆汁淤积性肝损伤。肝脏基因与蛋白表达分析证实齐墩果酸能够显著上调Mrp2, Mrp3, Mrp4表达,并且激活Nrf2,但对其它的胆汁酸转运体和代谢酶无显著影响。结果表明齐墩果酸能够预防和治疗石胆酸所诱导的胆汁淤积性肝损伤,机制涉及Nrf2-Mrp通路。
附图说明
图1为齐墩果酸逆转石胆酸所致小鼠存活率的下降结果图;
图2为齐墩果酸减轻石胆酸所致肝坏死程度结果图;
图3为齐墩果酸剂量依赖性逆转石胆酸所致小鼠血清生化指标的升高结果图;
图4为齐墩果酸剂量依赖性逆转石胆酸所致小鼠血中总胆汁酸和总胆红素,以及肝中总胆汁酸水平的升高结果图;
图5为齐墩果酸对小鼠胆汁酸胆汁酸转运体基因表达的影响结果图;
图6为齐墩果酸对小鼠胆汁酸代谢酶基因表达的影响结果图;
图7为齐墩果酸对Nrf2以及胆汁酸稳态调控相关核受体的影响结果图;
图8为齐墩果酸对小鼠Mrp转运体以及核内Nrf2蛋白表达的影响结果图。
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)材料与方法
1、主要仪器:
5417-R 低温高速离心机(德国Eppendorf公司);多功能酶标仪(美国Molecular devices公司);Mini-protein3电泳系统(美国Bio-Rad公司);Mini Trans-Blot转移系统(美国Bio-Rad公司);ImageQuant LAS 4000曝光成像仪(美国General Electric公司);梯度PCR仪(德国Eppendorf公司);7500 Real Time PCR System(美国Applied Biosystems公司)。
2、药品和试剂
齐墩果酸,石胆酸(纯度≥98%,上海阿拉丁试剂有限公司),玉米油(药用级,上海阿拉丁试剂有限公司);Pregnenolone-16α-Carbonitrile (PCN)(纯度≥98%,Sigma公司);ALT、AST、ALP、总胆汁酸、总胆红素检测试剂盒(南京建成生物工程研究所);小鼠Nrf2干扰序列(广州锐博公司);Trizol试剂、RT-PCR试剂盒,qRT-PCR试剂盒(Takara公司);Nrf2、Mrp2、Mrp3一抗(Santa cruz公司);Mrp4一抗(Abcam公司);RIPA裂解液、核蛋白提取试剂、BCA蛋白浓度测定试剂盒(江苏碧云天生物技术研究所);ECL发光液(北京英格恩生物科技公司);其它试剂均为分析纯级别。
(二)实验动物及给药方案
C57BL/6小鼠,雄性,周龄8-9周,由中山大学(大学城)实验动物中心提供,动物合格证号为SCXK(粤)2011-0029,正常小鼠用维持饲料喂养。齐墩果酸(5, 10, 20 mg/kg)溶于含2%吐温80的生理盐水;石胆酸(125 mg/kg)与PCN(50 mg/kg)溶于玉米油。小鼠随机分成7组,每组6-12只,组别为空白对照组、高剂量齐墩果酸组、石胆酸造模组、石胆酸+低剂量齐墩果酸组、石胆酸+中剂量齐墩果酸组、石胆酸+高剂量齐墩果酸组以及石胆酸+PCN组。齐墩果酸、石胆酸和PCN的给药方式均为腹腔注射,其中齐墩果酸与PCN连续给药7天,每天一次,而石胆酸在第四天开始协同给药,共给药4天,每天两次。最后一次给药后24h处理小鼠,计算每组小鼠存活率,解剖后对在体的肝脏及胆囊的形态进行拍照,然后收集血清以及肝脏,每组取三只小鼠部分肝脏置于10%甲醛中固定,其它样本在-80℃冷冻保存备用。
(三)肝组织与血清化学检测
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,血清中的ALT,
AST, ALP, 总胆汁酸,总胆红素以及肝脏中的总胆汁酸检测方法按照试剂盒的说明书来完成。
(四)qRT-PCR
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所述。
表1. 引物序列
Gene | Species | Genbank | Forward primer (5′→3′) | Reverse primer (5′→3′) |
Gapdh | Mouse | NM_008084 | AGGTCGGTGTGAACGGATTTG | GGGGTCGTTGATGGCAACA |
Ntcp | Mouse | NM_001177561 | CAAACCTCAGAAGGACCAAACA | GTAGGAGGATTATTCCCGTTGTG |
Oatp1b2 | Mouse | NM_020495 | GCACTGCGATGGATTCAGGAT | AGCTTTGGTCGGTGTAGCTTG |
Bsep | Mouse | NM_021022 | TCTGACTCAGTGATTCTTCGCA | CCCATAAACATCAGCCAGTTGT |
Mdr3 | Mouse | NM_011076 | AATGTTTCGTTATGCAGGTTGGC | TGGCTCTTTTATCGGCCTCAC |
Mrp2 | Mouse | NM_013806 | GTGTGGATTCCCTTGGGCTTT | CACAACGAACACCTGCTTGG |
Mrp3 | Mouse | NM_029600 | CTGGGTCCCCTGCATCTAC | GCCGTCTTGAGCCTGGATAAC |
Mrp4 | Mouse | NM_001033336 | CATCGCGGTAACCGTCCTC | CCGCAGTTTTACTCCGCAG |
Cyp7a1 | Mouse | NM_007824 | GAACCTCCTTTGGACAACGGG | GGAGTTTGTGATGAAGTGGACAT |
Cyp3a11 | Mouse | NM_007818 | GGATGAGATCGATGAGGCTCTG | CAGGTATTCCATCTCCATCACAGT |
Cyp2b10 | Mouse | NM_009999 | TGCTGTCGTTGAGCCAACC | CCACTAAACATTGGGCTTCCT |
Sult2a1 | Mouse | NM_001111296 | GAAGGCATACCTTTTCCTGCCAT | GTAACCAGACACAAGAATATCTCT |
Ugt1a1 | Mouse | NM_201645 | GCTTCTTCCGTACCTTCTGTTG | GCTGCTGAATAACTCCAAGCAT |
Nrf2 | Mouse | NM_010902 | CTTTAGTCAGCGACAGAAGGAC | AGGCATCTTGTTTGGGAATGTG |
Fxr | Mouse | NM_001163504 | GCTTGATGTGCTACAAAAGCTG | CGTGGTGATGGTTGAATGTCC |
Pxr | Mouse | NM_010936 | GATGGAGGTCTTCAAATCTGCC | CAGCCGGACATTGCGTTTC |
Car | Mouse | NM_001243062 | TTCAAGCCTCCGGCCTATCT | TGATCTGTTGCACCATAAACGTG |
(五)Western blot
按照RIPA裂解液或者核蛋白提取试剂盒的说明书得到相应的组织总蛋白或者核蛋白产物,蛋白浓度测定采用BCA法,蛋白分离过程中,聚丙烯酰胺凝胶的浓度为8%,分离后的蛋白转移到PVDF膜中,然后用含5%脱脂奶粉的TBST溶液常温下封闭1h,再分别用不同的一抗(Gapdh, Mrp2, Mrp3, Mrp4,
Nrf2)在4℃孵育过夜,之后用TBST洗膜两次,每次5min,然后在常温下分别孵育相应来源的二抗1h,再接着用TBST洗膜三次,每次5min,最后按照ECL发光液的说明书曝光得到蛋白条带。
(六)数据统计
各组实验数据均以mean ±
S.E.M. 表示,采用GraphPad Prism 5 软件进行统计分析,采用unpaired Student’s t test进行两组间比较,P < 0.05被认为有显著性差异。
(七)实验结果
1、齐墩果酸逆转石胆酸所致小鼠存活率的下降
如图1所示,与空白对照组比较,齐墩果酸20 mg/kg组的小鼠无死亡,提示单用齐墩果酸不影响小鼠存活率,但是石胆酸造模组的小鼠存活率降为58%,提示石胆酸具有明显的毒性作用,能够显著地降低小鼠存活率。与石胆酸造模组比较,分别协同给予5,10,20 mg/kg的齐墩果酸或者50 mg/kg PCN组的小鼠存活率分别为90%,80%,100%,100%,提示5~20
mg/kg剂量的齐墩果酸以及PCN均能显著地逆转石胆酸所致小鼠存活率的降低。
2、墩果酸减轻石胆酸所致肝坏死程度
如图2A所示,与空白对照组相比,石胆酸造模组小鼠的肝脏解剖在体观察发现明显的肝坏死病理改变,表现为肝包膜下出现无数明显的白色的坏死病灶点,同时胆囊呈现异常的扩张。协同给予20 mg/kg齐墩果酸或者50 mg/kg PCN组小鼠肝包膜下的坏死病灶点数目明显减少,肝脏形态趋于正常,而且胆囊恢复至正常形态。如图2B所示,H&E染色结果显示与空白对照组相比,石胆酸造模组小鼠出现大面积的肝细胞坏死。协同给予20 mg/kg齐墩果酸或者50 mg/kg PCN组小鼠无显著的肝细胞坏死。图2A和2B提示齐墩果酸能显著减轻石胆酸所致肝坏死的程度。
3、齐墩果酸剂量依赖性逆转石胆酸所致小鼠血清生化指标的升高
如图3所示,与空白对照组相比,石胆酸造模组小鼠的ALT、AST和ALP水平分别上升至4147, 4910 和437 U/L,提示石胆酸能够造成严重的肝损伤以及胆管损伤。分别协同给予5,10,20 mg/kg的齐墩果酸能剂量依赖性的逆转石胆酸诱导的ALT、AST和ALP水平上调,其中ALT水平分别降至石胆酸造模组的39%,22% 和14%;AST水平降至石胆酸造模组的33%,14% 和6%;ALP水平降至石胆酸造模组的71%,69% 和42%。该结果提示齐墩果酸能剂量依赖性的保护石胆酸所致小鼠的肝损伤和胆管损伤。
4、齐墩果酸剂量依赖性逆转石胆酸所致小鼠血中总胆汁酸和总胆红素,以及肝中总胆汁酸水平的升高
如图4所示,与空白对照组相比,石胆酸造模组的小鼠血中总胆汁酸和总胆红素水平上升了17倍和32倍,同时肝中总胆汁酸水平上升了3倍,提示石胆酸能导致严重的胆汁淤积。分别协同给予5,10,20 mg/kg的齐墩果酸能剂量依赖性的逆转石胆酸诱导的血中总胆汁酸和总胆红素,以及肝中总胆汁酸水平上调,其中,血中总胆汁酸水平降至石胆酸造模组的47%, 47% and 35%;血中总胆红素水平降至石胆酸造模组的27%,24 % 和 14%,提示齐墩果酸能剂量依赖性的减轻石胆酸所致小鼠的胆汁淤积。
5、齐墩果酸对小鼠胆汁酸稳态调控相关基因表达的影响
如图5-7所示,共检测了与胆汁酸稳态相关的16个基因的表达,其中包括核受体(PXR,CAR,FXR),Nrf2,基底侧胆汁酸摄入转运体(Oatp1b2,Ntcp),基底侧胆汁酸外排转运体(Mrp3,Mrp4),胆管侧胆汁酸外排转运体(Bsep,Mrp2,Mdr3),胆汁酸代谢酶(Cyp7a1,Sult2a1,Ugt1a1,Cyp3a11,Cyp2b10)。检测结果显示齐墩果酸能显著上调Mrp2,Mrp3,Mrp4以及Nrf2的mRNA水平,但对其它胆汁酸相关核受体,转运体或者代谢酶的影响无显著性差异。该结果提示齐墩果酸预防与治疗胆汁淤积症作用的机制可能涉及Mrp2,Mrp3,Mrp4介导的肝脏中胆汁酸外排增加,而不影响肝脏中胆汁酸的摄入和代谢水平,同时由于Nrf2能同时调控Mrp2,Mrp3,Mrp4的表达,Nrf2可能参与介导胆汁酸外排的增加。
6、齐墩果酸对小鼠Mrp转运体以及核内Nrf2蛋白表达的影响
如图8A所示,与空白对照组相比,石胆酸造模组的小鼠Mrp3和Mrp4蛋白表达水平显著上调,Mrp2蛋白表达水平显著下调,而核内Nrf2蛋白表达无显著性差异。与石胆酸造模组相比,协同齐墩果酸给药组小鼠的Mrp3和Mrp4蛋白表达水平上调更加明显,Mrp2蛋白表达水平恢复致正常水平,核内Nrf2蛋白表达水平显著性上调。此外,单独给予齐墩果酸组小鼠的Mrp2,Mrp3,Mrp4以及核内Nrf2蛋白表达水平与空白对照组相比,均呈现显著性的上调。该结果提示齐墩果酸能激活Nrf2,同时上调Nrf2的下游靶基因Mrp2,Mrp3,Mrp4的蛋白表达量。图8B为图6A中蛋白条带的定量统计结果。该蛋白水平的结果与基因水平结果一致。
Claims (8)
1.齐墩果酸在制备预防和治疗胆汁淤积症药物中的应用,其特征在于,所述胆汁淤积症是指石胆酸诱导的胆汁淤积症,所述药物还包括药物载体。
2.根据权利要求1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。
3.根据权利要求2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;所述黏合剂为藻酸盐、明胶、淀粉浆或聚乙烯吡咯烷酮。
4.根据权利要求2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。
5.根据权利要求2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。
6.根据权利要求2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。
7.根据权利要求1-6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。
8.根据权利要求1-6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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