中药肝毒性及评价技术方法研究进展
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摘要
中药的肝毒性是中医药界关注的重要问题。正确认识和评价具有肝毒性的中药,探索中药肝毒性早期生物标志物,从而保证临床用药安全。本文从肝毒性中药的毒性成分、毒性机制以及评价中药肝毒性的技术和方法进行综述。对血清酶学生物标志物以及系统生物学技术、microRNAs芯片技术在中药肝毒性研究中的应用进行展望,为中药肝毒性的研究提供参考。
The hepatotoxicity of traditional Chinese medicine( TCM) is focus on the important problem in the field of medicine. We should understand and evaluate correctly TCM with liver toxicity and explore early biomarkers on the hepatotoxicity of TCM,in order to ensure clinical medication safety. This paper summaried the poisonous components on the liver toxicity of TCM,toxicity mechanism and evaluation technology and methods on the hepatotoxicity of TCM. Serum enzyme biomarkers and systems biology technology,microRNAs chip technology in the application of the liver toxicity of TCM studies were discussed,which could provide a reference for the studies on the hepatotoxicity of TCM.
The hepatotoxicity of traditional Chinese medicine( TCM) is focus on the important problem in the field of medicine. We should understand and evaluate correctly TCM with liver toxicity and explore early biomarkers on the hepatotoxicity of TCM,in order to ensure clinical medication safety. This paper summaried the poisonous components on the liver toxicity of TCM,toxicity mechanism and evaluation technology and methods on the hepatotoxicity of TCM. Serum enzyme biomarkers and systems biology technology,microRNAs chip technology in the application of the liver toxicity of TCM studies were discussed,which could provide a reference for the studies on the hepatotoxicity of TCM.
引文
1顾立强,马冰洁,孟夏,等.中药肝毒性及肝脏保护作用的研究方法进展.中国药物警戒,2013;10(7)∶408~410
2王学勤,李丰林,张维国.中药药物性肝损害研究进展.亚太传统医药,2015;11(5)∶35~36
3王秀娟,许利平,王敏.常用中药及复方制剂的肝毒性.首都医科大学学报,2007;28(2)∶220~224
4 Teschke R.Traditional Chinese Medicine inducedliver injury.J Clin Transl Hepatol,2014;2(2)∶80~94
5 Navarro VJ,Senior JR.Drug-related hepatotoxicity.N Engl J Med,2006;354(7)∶731~739
6 Li B,Wang Z,Fang JJ,et al.Evaluation of prognostic markers in severe drug-induced liver disease.World J Gastroenterol,2007;13(4)∶628~632
7徐静,王茂荣.土三七导致肝小静脉闭塞综合征研究进展.实用肝脏病杂志,2013;16(1)∶94~96
8王军,王长虹,王峥涛.吡咯里西啶生物碱的细胞毒性及致毒机制研究进展.国际药学研究杂志,2007;34(4)∶246~258
9汤俊,服部征雄.《中国药典》含吡咯里西啶生物碱的中药品种与用药安全.药学学报,2011;46(7)∶1~6
10程敏,汤俊,高秋芳.等.川紫菀水提取物中主要生物碱成分clivorine分析及其对大鼠肝毒性初步研究.中草药,2011;42(12)∶2507~2511
11郑艳春,秦婷,崔雅慧,等.北豆根化学成分及其药理作用的研究进展.中国医药导报,2011;8(13)∶9~10
12童晓东.山豆根与北豆根的药用比较.国医论坛,2002;17(6)∶41~42
13周倩,金若敏,姚广涛,等.蝙蝠葛碱体外肝肾细胞毒性的初步研究.中国药物警戒,2012;(10)∶580~583
14张丽华,吕莉莉,张亚囡,等.柴胡总皂苷肝毒性肝纤维化损伤机制研究.中国药物警戒,2012;9(11)∶652~655
15黄伟,吕丽莉,孙蓉,等.柴胡总皂苷粗提物致大鼠肝毒性氧化损伤机制研究.中草药,2009;40(增刊)∶8~13
16吕天,牟红元,冯江江,等.中药柴胡总皂苷急性肝毒性的代谢组学研究.化学研究与应用,2013;25(6)∶789~792
17刘若囡,徐立,时乐,等.常用皂苷类中药致肝损伤的毒理学研究进展.中南药学,2010;8(12)∶916~919
18 Man S,Qiu P,Li J,et al.Global metabolic profiling for the study of Rhizoma Paridis saponins-induced hepatotoxicityin rats.Environ Toxicol,2015;11(epub ahead of print)
19 Ding Y,Zhang T,Tao JS,et al.Potential hepatotoxicity of geniposide,the major iridoid glycoside in dried ripe fruits of Gardenia jasminoides(Zhizi).Nat Prod Res,2013;27(10)∶929~933
20程生辉,唐超,李会芳,等.栀子苷对正常大鼠急性肝、肾毒性的时-毒关系分析.中国实验方剂学杂志,2016;22(1)∶162~165
21刘红杰,金若敏,张文斌,等.薄荷油致大鼠肝毒性时量关系及对肝细胞超微结构的影响.中国药理学通报,2008;4(1)∶4~6
22熊彦红,齐双岩,金若敏,等.川楝子对大鼠肝毒性的时效和量效关系研究.江苏中医药,2008;40(7)∶83~85
23王建平.大黄有毒物质基础的研究.中国民族民间医药,2011;24∶63~64
24 Lynch T,Price A.The effect of cytochrome P450 metabolism on drug response,interactions,and adverse effects.Am Fam Physician,2007;76(3)∶391~396
25乔靖怡,金若敏,姚广涛,等.山豆根致大鼠肝损伤对肝细胞色素P450酶的影响.中国实验方剂学杂志,2014;20(18)∶132~135
26光吉博则,谷仁烨.氧化应激的病理生理作用.日本医学介绍,2007;28∶150~152
27刘丹卓,赵新广.肝损伤病因病理机制及中医药治疗研究近况.国医论坛,2006;21(6)∶53~55
28 Ramachandran A,Lebofsky M,Weinman SA,et al.The impact of partial manganese superoxide dismutase(SOD2)-deficiency on mitochondrial oxidant stress,DNA fragmentation and liver injury during acetaminophen hepatotoxicity.Toxicol Appl Pharmacol,2011;251(3)∶226~233
29 Zhang J1,Li Y,Jiang S,et al.Enhanced endoplasmic reticulum SERCAactivity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis.Am J Physiol Cell Physiol,2014;306(3)∶c279~c290
30 Marrer E,Dieterle F.Impact of biomarker development on drug safety assessment.Toxicol Appl Pharmacol,2010;243(2)∶167~179
31孔明,戴菁,孙旖,等.药物性肝损伤生物标志物研究进展.中国新药杂志,2013;22(3)∶290~292
32 Ozer J,Ratner M,Shaw M,et al.The current state of serum biomarkers of hepatotoxicity.Toxicology,2008;245(3)∶194~205
33耿兴超,沈连忠,李波,等.肝毒性生物标志物研究进展.中国药学杂志,2011;46(10)∶721~725
34刘晓娜,刘密凤,贾栗.药源性肝损伤潜在血清生物标志物的研究进展.首都医科大学学报,2014;35(4)∶511~515
35唐勇,李锐.联合检测血清胆碱酯酶、总胆汁酸对肝病临床诊断价值的应用.国际检验医学杂志,2009;30(5)∶506~508
36盛云华,金若敏,姚广涛,等.黄药子醇提物致大鼠肝损伤血清总胆汁酸早期变化研究.中药药理与临床,2012;28(1)∶118~121
37 Muller PY,Dieterle F.Tissue-specific,non-invasive toxicity biomarkers∶translation from preclinical safety assessment to clinical safety monitoring.Expert Opin Drug Metab Toxicol,2009;5(9)∶1023~1038
38 Frederiks WM,Bosch KS,Van Gulik T.A quantitative histochemical procedure for the demonstration of purine nucleoside phosphorylase activity in rat and human liver using Teranitro BT and xantheine oxidase as auxillaryenzyme.Histochem J,1993;25(1)∶86~91
39乔靖怡,周璐,金若敏,等.四氯化碳致大鼠肝损伤早期血清总胆汁酸、α-谷胱甘肽S转移酶、嘌呤核苷磷酸化酶和鸟氨酸氨基甲酰转移酶的变化.中国药理学与毒理学杂志,2013;27(4)∶650~656
40黄幼异,孙蓉.系统生物学技术用于中药肝毒性发现与评价的研究进展.中国药物警戒,2013;10(4)∶219~222
41 Nicholson JK,Lindon JC,Holmes E.'Metabonomics'∶understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.Xenobiotica,1999;29(11)∶1181~1189
42 Valencia-Sanchez MA,Liu J,Hannon GJ,et al.Control of translation and RNA degradation by miRNAs and siRNAs.Genes Dev,2006;20(5)∶515~524
43 Vickers K C,Remaley A T.MicroRNAs in atherosclerosis and lipoprotein metabolism.Curr Opin Endocrinol Diabrtes Obes,2010;17(2)∶150~155
44乔靖怡,金若敏.MicroRNAs作为生物标志物的研究进展.中国中药杂志,2012;37(15)∶2202~2205
45 Wang K,Zhang S,Marzolf B,et al.Circulating microRNAs,potential biomarkers for drug-induced liver injury.Proc Natl Acad Sci U S A,2009;106(11)∶4402~4407
46 Starkey Lewis PJ,Dear J,Platt V,et al.Circulating microRNAs as potential markers of human drug-induced liver injury.Hepatology,2011;54(5)∶1767~1776
47 Su YW,Chen X,Jiang ZZ,et al.A panel of serum microRNAs as specific biomarkers for diagnosis of compound-and herb-induced liver injury in rats.PLoS One,2012;7(5)∶e37395
2王学勤,李丰林,张维国.中药药物性肝损害研究进展.亚太传统医药,2015;11(5)∶35~36
3王秀娟,许利平,王敏.常用中药及复方制剂的肝毒性.首都医科大学学报,2007;28(2)∶220~224
4 Teschke R.Traditional Chinese Medicine inducedliver injury.J Clin Transl Hepatol,2014;2(2)∶80~94
5 Navarro VJ,Senior JR.Drug-related hepatotoxicity.N Engl J Med,2006;354(7)∶731~739
6 Li B,Wang Z,Fang JJ,et al.Evaluation of prognostic markers in severe drug-induced liver disease.World J Gastroenterol,2007;13(4)∶628~632
7徐静,王茂荣.土三七导致肝小静脉闭塞综合征研究进展.实用肝脏病杂志,2013;16(1)∶94~96
8王军,王长虹,王峥涛.吡咯里西啶生物碱的细胞毒性及致毒机制研究进展.国际药学研究杂志,2007;34(4)∶246~258
9汤俊,服部征雄.《中国药典》含吡咯里西啶生物碱的中药品种与用药安全.药学学报,2011;46(7)∶1~6
10程敏,汤俊,高秋芳.等.川紫菀水提取物中主要生物碱成分clivorine分析及其对大鼠肝毒性初步研究.中草药,2011;42(12)∶2507~2511
11郑艳春,秦婷,崔雅慧,等.北豆根化学成分及其药理作用的研究进展.中国医药导报,2011;8(13)∶9~10
12童晓东.山豆根与北豆根的药用比较.国医论坛,2002;17(6)∶41~42
13周倩,金若敏,姚广涛,等.蝙蝠葛碱体外肝肾细胞毒性的初步研究.中国药物警戒,2012;(10)∶580~583
14张丽华,吕莉莉,张亚囡,等.柴胡总皂苷肝毒性肝纤维化损伤机制研究.中国药物警戒,2012;9(11)∶652~655
15黄伟,吕丽莉,孙蓉,等.柴胡总皂苷粗提物致大鼠肝毒性氧化损伤机制研究.中草药,2009;40(增刊)∶8~13
16吕天,牟红元,冯江江,等.中药柴胡总皂苷急性肝毒性的代谢组学研究.化学研究与应用,2013;25(6)∶789~792
17刘若囡,徐立,时乐,等.常用皂苷类中药致肝损伤的毒理学研究进展.中南药学,2010;8(12)∶916~919
18 Man S,Qiu P,Li J,et al.Global metabolic profiling for the study of Rhizoma Paridis saponins-induced hepatotoxicityin rats.Environ Toxicol,2015;11(epub ahead of print)
19 Ding Y,Zhang T,Tao JS,et al.Potential hepatotoxicity of geniposide,the major iridoid glycoside in dried ripe fruits of Gardenia jasminoides(Zhizi).Nat Prod Res,2013;27(10)∶929~933
20程生辉,唐超,李会芳,等.栀子苷对正常大鼠急性肝、肾毒性的时-毒关系分析.中国实验方剂学杂志,2016;22(1)∶162~165
21刘红杰,金若敏,张文斌,等.薄荷油致大鼠肝毒性时量关系及对肝细胞超微结构的影响.中国药理学通报,2008;4(1)∶4~6
22熊彦红,齐双岩,金若敏,等.川楝子对大鼠肝毒性的时效和量效关系研究.江苏中医药,2008;40(7)∶83~85
23王建平.大黄有毒物质基础的研究.中国民族民间医药,2011;24∶63~64
24 Lynch T,Price A.The effect of cytochrome P450 metabolism on drug response,interactions,and adverse effects.Am Fam Physician,2007;76(3)∶391~396
25乔靖怡,金若敏,姚广涛,等.山豆根致大鼠肝损伤对肝细胞色素P450酶的影响.中国实验方剂学杂志,2014;20(18)∶132~135
26光吉博则,谷仁烨.氧化应激的病理生理作用.日本医学介绍,2007;28∶150~152
27刘丹卓,赵新广.肝损伤病因病理机制及中医药治疗研究近况.国医论坛,2006;21(6)∶53~55
28 Ramachandran A,Lebofsky M,Weinman SA,et al.The impact of partial manganese superoxide dismutase(SOD2)-deficiency on mitochondrial oxidant stress,DNA fragmentation and liver injury during acetaminophen hepatotoxicity.Toxicol Appl Pharmacol,2011;251(3)∶226~233
29 Zhang J1,Li Y,Jiang S,et al.Enhanced endoplasmic reticulum SERCAactivity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis.Am J Physiol Cell Physiol,2014;306(3)∶c279~c290
30 Marrer E,Dieterle F.Impact of biomarker development on drug safety assessment.Toxicol Appl Pharmacol,2010;243(2)∶167~179
31孔明,戴菁,孙旖,等.药物性肝损伤生物标志物研究进展.中国新药杂志,2013;22(3)∶290~292
32 Ozer J,Ratner M,Shaw M,et al.The current state of serum biomarkers of hepatotoxicity.Toxicology,2008;245(3)∶194~205
33耿兴超,沈连忠,李波,等.肝毒性生物标志物研究进展.中国药学杂志,2011;46(10)∶721~725
34刘晓娜,刘密凤,贾栗.药源性肝损伤潜在血清生物标志物的研究进展.首都医科大学学报,2014;35(4)∶511~515
35唐勇,李锐.联合检测血清胆碱酯酶、总胆汁酸对肝病临床诊断价值的应用.国际检验医学杂志,2009;30(5)∶506~508
36盛云华,金若敏,姚广涛,等.黄药子醇提物致大鼠肝损伤血清总胆汁酸早期变化研究.中药药理与临床,2012;28(1)∶118~121
37 Muller PY,Dieterle F.Tissue-specific,non-invasive toxicity biomarkers∶translation from preclinical safety assessment to clinical safety monitoring.Expert Opin Drug Metab Toxicol,2009;5(9)∶1023~1038
38 Frederiks WM,Bosch KS,Van Gulik T.A quantitative histochemical procedure for the demonstration of purine nucleoside phosphorylase activity in rat and human liver using Teranitro BT and xantheine oxidase as auxillaryenzyme.Histochem J,1993;25(1)∶86~91
39乔靖怡,周璐,金若敏,等.四氯化碳致大鼠肝损伤早期血清总胆汁酸、α-谷胱甘肽S转移酶、嘌呤核苷磷酸化酶和鸟氨酸氨基甲酰转移酶的变化.中国药理学与毒理学杂志,2013;27(4)∶650~656
40黄幼异,孙蓉.系统生物学技术用于中药肝毒性发现与评价的研究进展.中国药物警戒,2013;10(4)∶219~222
41 Nicholson JK,Lindon JC,Holmes E.'Metabonomics'∶understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.Xenobiotica,1999;29(11)∶1181~1189
42 Valencia-Sanchez MA,Liu J,Hannon GJ,et al.Control of translation and RNA degradation by miRNAs and siRNAs.Genes Dev,2006;20(5)∶515~524
43 Vickers K C,Remaley A T.MicroRNAs in atherosclerosis and lipoprotein metabolism.Curr Opin Endocrinol Diabrtes Obes,2010;17(2)∶150~155
44乔靖怡,金若敏.MicroRNAs作为生物标志物的研究进展.中国中药杂志,2012;37(15)∶2202~2205
45 Wang K,Zhang S,Marzolf B,et al.Circulating microRNAs,potential biomarkers for drug-induced liver injury.Proc Natl Acad Sci U S A,2009;106(11)∶4402~4407
46 Starkey Lewis PJ,Dear J,Platt V,et al.Circulating microRNAs as potential markers of human drug-induced liver injury.Hepatology,2011;54(5)∶1767~1776
47 Su YW,Chen X,Jiang ZZ,et al.A panel of serum microRNAs as specific biomarkers for diagnosis of compound-and herb-induced liver injury in rats.PLoS One,2012;7(5)∶e37395