四种药物致Balb/c小鼠肝脏毒性的基因表达谱研究
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摘要
药物不良反应是长期以来危害人体健康的一个医学难题,当前各国由药物不良反应所引发的疾病都呈上升趋势,同时它也是众多新药开发和临床运用的难题和障碍,对药物毒性机制进行深入研究有重要的医学和社会意义,但传统的药物毒理学研究缺乏在分子水平上进行综合分析的手段,使药物毒理研究与发展相对滞后。
毒理基因组学为药物毒理研究引入了新的研究理论和技术手段,基因芯片等高通量基因组技术手段可以同时观察药物毒性作用引发的数以千计的基因的表达变化模式,而这种基因表达谱上所显现的毒性终点往往具有较好的敏感性和特异性,有助于对毒性机制的阐明。目前此方面工作正在广泛开展并取得许多成果。肝脏是人体药物代谢的主要器官,药物引发的肝毒性损伤占临床药物不良反应的相当比例,因此众多研究均从药物肝毒性动物模型入手。
本课题是以本室与香港城市大学联合构建的小鼠毒理基因芯片为技术平台,建立四种具肝毒性效应的临床药物(红霉素、四环素、环磷酰胺、异环磷酰胺)的Balb/c小鼠肝毒性模型,对比研究各药物作用后不同时相点和剂量点小鼠肝脏基因表达谱变化,为在分子水平上探索药物肝脏毒性作用机制积累资料,同时验证本实验室与香港城市大学联合构建的小鼠毒理基因芯片用于药物毒性评价的可行性。本研究分为三部分进行:第一部分,建立四种药物致Balb/c小鼠肝毒性损伤模型;第二部分,设计制作小鼠毒理基因芯片,建立相应芯片检测流程,并进行相关质控分析和可靠性验证;第三部分,利用小鼠毒理基因芯片观察各实验组小鼠肝脏基因表达谱变化,并结合聚类分析及生物信息数据库检索等手段对数据进行初步分析,探讨药物致肝脏毒性的作用机制。主要的结果如下:
1.本研究建立了红霉素、四环素、环磷酰胺和异环磷酰胺四种药物的Balb/c小鼠不同时相和剂量的肝毒性作用模型,体重指标统计发现多个药物组动物平均体重下降,提示动物机体能量代谢障碍;各组动物血浆肝功生化指标和肝脏病理切片观察发现各药物引起肝脏不同程度和类型的毒性损伤。
2.挑选与环境化合物致癌、外来化合物/药物代谢及毒性效应相关的1796个基因片段,构建小鼠毒理基因芯片及配套数据库。
The adverse drug reaction (ADR) is a difficult medical problem harmed the humanity health since long ago.The diseases caused by ADR in various countries are on the rise at present , furthermore, ADR is a huge barrier for the the new medicine research and clinical exertion.It has important medical and social significance for carrying on further research on toxic mechanism of medicine. Whereas,there are littler synthetical analyse measure on the molecule level in the traditional medicine toxicology, which result the slowly developing in medicine toxicology studying .
Toxicogenomics supply a new technological means and research idea for the medicine toxicology. Gene chip ,which is a high flux genome-based technology , can observe simultaneously thousands gene expression model induced by drug toxic effect, and the toxicity endpoints appeared from the gene expression profile generally are more sensitive and differential that in favor of elucidating the toxicity mechanism.This research work has extensively launched and make a lot of achievements in this respect at present. The liver is a main organ of the human drug metabolism, and the liver damages induced by drug toxicity are high percentage in clinic ADR.Therefore many correlative studying are focus on drug hepatotoxicity.
The objective of this experimental study is comparely studying the gene expression profile at different time phases and dosages after drug treated, which based on the balb/c mice hepatotoxic model caused by erythromycin lactobionate, tetracycline hydrochloride, cyclophosphamide, ifosfamide ,and on the mouse toxicology gene chip , accumulating data for the drug hepatotoxicity mechanism on molecule level, and validating the feasibility of the mouse toxicology gene chip applying on drug toxicity evaluation. The experimental study was composed of three parts:⑴Establishing the balb/c mice hepatotoxic model caused by erythromycin lactobionate, tetracycline hydrochloride, cyclophosphamide and ifosfamide.⑵Establishing and evaluating the technique of detection for the mouse
毒理基因组学为药物毒理研究引入了新的研究理论和技术手段,基因芯片等高通量基因组技术手段可以同时观察药物毒性作用引发的数以千计的基因的表达变化模式,而这种基因表达谱上所显现的毒性终点往往具有较好的敏感性和特异性,有助于对毒性机制的阐明。目前此方面工作正在广泛开展并取得许多成果。肝脏是人体药物代谢的主要器官,药物引发的肝毒性损伤占临床药物不良反应的相当比例,因此众多研究均从药物肝毒性动物模型入手。
本课题是以本室与香港城市大学联合构建的小鼠毒理基因芯片为技术平台,建立四种具肝毒性效应的临床药物(红霉素、四环素、环磷酰胺、异环磷酰胺)的Balb/c小鼠肝毒性模型,对比研究各药物作用后不同时相点和剂量点小鼠肝脏基因表达谱变化,为在分子水平上探索药物肝脏毒性作用机制积累资料,同时验证本实验室与香港城市大学联合构建的小鼠毒理基因芯片用于药物毒性评价的可行性。本研究分为三部分进行:第一部分,建立四种药物致Balb/c小鼠肝毒性损伤模型;第二部分,设计制作小鼠毒理基因芯片,建立相应芯片检测流程,并进行相关质控分析和可靠性验证;第三部分,利用小鼠毒理基因芯片观察各实验组小鼠肝脏基因表达谱变化,并结合聚类分析及生物信息数据库检索等手段对数据进行初步分析,探讨药物致肝脏毒性的作用机制。主要的结果如下:
1.本研究建立了红霉素、四环素、环磷酰胺和异环磷酰胺四种药物的Balb/c小鼠不同时相和剂量的肝毒性作用模型,体重指标统计发现多个药物组动物平均体重下降,提示动物机体能量代谢障碍;各组动物血浆肝功生化指标和肝脏病理切片观察发现各药物引起肝脏不同程度和类型的毒性损伤。
2.挑选与环境化合物致癌、外来化合物/药物代谢及毒性效应相关的1796个基因片段,构建小鼠毒理基因芯片及配套数据库。
The adverse drug reaction (ADR) is a difficult medical problem harmed the humanity health since long ago.The diseases caused by ADR in various countries are on the rise at present , furthermore, ADR is a huge barrier for the the new medicine research and clinical exertion.It has important medical and social significance for carrying on further research on toxic mechanism of medicine. Whereas,there are littler synthetical analyse measure on the molecule level in the traditional medicine toxicology, which result the slowly developing in medicine toxicology studying .
Toxicogenomics supply a new technological means and research idea for the medicine toxicology. Gene chip ,which is a high flux genome-based technology , can observe simultaneously thousands gene expression model induced by drug toxic effect, and the toxicity endpoints appeared from the gene expression profile generally are more sensitive and differential that in favor of elucidating the toxicity mechanism.This research work has extensively launched and make a lot of achievements in this respect at present. The liver is a main organ of the human drug metabolism, and the liver damages induced by drug toxicity are high percentage in clinic ADR.Therefore many correlative studying are focus on drug hepatotoxicity.
The objective of this experimental study is comparely studying the gene expression profile at different time phases and dosages after drug treated, which based on the balb/c mice hepatotoxic model caused by erythromycin lactobionate, tetracycline hydrochloride, cyclophosphamide, ifosfamide ,and on the mouse toxicology gene chip , accumulating data for the drug hepatotoxicity mechanism on molecule level, and validating the feasibility of the mouse toxicology gene chip applying on drug toxicity evaluation. The experimental study was composed of three parts:⑴Establishing the balb/c mice hepatotoxic model caused by erythromycin lactobionate, tetracycline hydrochloride, cyclophosphamide and ifosfamide.⑵Establishing and evaluating the technique of detection for the mouse
引文
1. 蔡卫民.药物不良反应遗传背景与个体化合理用药. 中国处方药. 2005;37(4) :10-15.
2. WHO 国际药物监测合作计划发展概况 药物不良反应杂志 1999;1:47 .
3. Farr S, Dunn RT. Concise review:gene expression applied to toxicology. Toxicol Sci. 1999;50(1):1-9.
4. Corton JC, Stauber AJ. et al. Toward construction of a transcript profile database predictive of chemical toxicity. Toxicol Sci. 2000;58(2):217-219.
5. Nuwaysir EF, Bittner M, Trent J, et al. Microarrays and toxicology: the advent of toxicogenomics. Mol Carcinog. 1999;24(3):153-159.
6. 陈小朋编译. 基因组学及相关组学技术对药物毒理学的影响. 国外医学药学分册.2002;29(5):261-264.
7. Hamadeh HK, Bushel PR, Jayadev S, et al. Prediction of Compound Signature Using High Density Gene Expression Profiling. Toxicol Sci, 2002;67:232-240.
8. Lu AY. Drug metabolism research challenges in the new millennium. Drug Metab Dispos. 1998;26(12):1217-1222.
9. Hirvonen A. Polymorphisms of xenobiotic metabolizing enzymes and susceptibility to cancer. Environ Health Perspect. 1999;107(Suppl):37-47.
10. Mc Carthy JJ, Hilfiker R. The use of single nucleotide polymorphism maps in pharmacogenomics. Nat Biotechnol,2 000; 8∶505-508.
11. Ganter B, Tugendreich S, Pearson CI,et al. Development of a large-scale chemogenomics database to improve drug candidate selection and to understand mechanisms of chemical toxicity and action.J Biotechnol. 2005; 119(3):219-244.
12. Baker TK, Carfagna MA, Gao H ,et al. Temporal gene expression analysis of monolayer cultured rat hepatocytes. Chem Res Toxicol. 2001;14: 1218-1231.
13. Mattes WB, Pettit SD, Sansone SA, et al. Database Development in Toxicogenomics: Issues and Efforts.Environ Health Perspect. 2004;112(4):495-505.
14. Waring JF, Jolly RA, Ciurlionis R, et al .Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles. Toxicol. Appl. Pharmacol. 2001; 175 :28–42.
15. Steiner G, Suter L, Boess F, et al .Discriminating different classes of toxicants by transcript profiling,.Environ. Health Perspect. 2004; 112: 1236–1248.
16. Freeman K. Toxicogenomics data: the road to acceptance. Environ.Health Perspect. 2004; 112 :A678–A685.
17. Morgan KT, Jayyosi Z, Hower MA, et al .The hepatic transcriptome as a window on whole-body physiology and pathophysiology. Toxicol Pathol. 2005;33(1):136-145.
18. Larrey D.Epidemiology and individual susceptibility to adverse drug reactions afecting the liver.Seminars in liver Disease.2002;22(2):145-55.
19. Lewis JH, Zimmerman HJ. Drug-induced liver disease. Med Clin North Am. 1989 ;73(4):775-792.
20. Ostapowicz G,Fontana RJ,Larson AM,et a1.Etiology and outcome of acute liver failure in the USA : preliminary results of prospective multicenter study.Hepatology.1999; 30:221 A.
21. Larry D. Drug-induced liver disease.J Hepatol 2000; 32:77-88.
22. Jaeschke H, Gores GJ, Cederbaum AI, et al.Mechanisms of hepatotoxicity. Toxicol Sci. 2002;65(2):166-176.
23. Maddrey WC.Drug-induced hepatotoxicity: 2005. J Clin Gastroenterol. 2005 ;39(4 Suppl 2):S83-89.
24. Gerhold D,Lu M, Xu J, et al.Monitoring expression of genes involved in drug metabolism and toxicology using DNA microarrays. Physiol Genomics.2001;5: 161–170.
25. Reilly T.P, Bourd M, Brady JN, et al. Expression profiling of acetaminophen liver toxicity in mice using microarray technology. Biochem. Biophys. Res. Commun. 2001;282:321–328.
26. Waring JF, Ciurlionis R, Jolly RA,et al. Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity, Toxicol. Lett. 2001;120:359–368.
27. Bulera SJ,.Eddy SM, Ferguson E, et al.RNA expression in the early characterization of hepatotoxicants in Wistar rats by high-density DNA microarrays, Hepatology 2001;33:1239–1258.
28. Thomas RS, Rank DR, Penn SG, et al Identification of toxicologically predictive genesets using cDNA microarrays, Mol. Pharmacol. 2001;60: 1189–1194.
29. Amacher DE, Schomaker SJ, Retsema JA. Comparison of the effects of the new azalide antibiotic azithromycin and erythromycin estolate on liver cytochrome P.450. J Antimicrob Chemother.1991;35(6):1186–1190.
30. Carevic O, Prpic V, Sverko V. Correlation between erythromycin and acid phosphatase in mouse liver. Biochim Biophys Acta. 1975;381(2):269-277.
31. Venkateswaran S, Pari L, Viswanathan P. Antiperoxidative effect of Livex, a herbal formulation against erythromycin estolate induced lipid peroxidation in rats. Phytother Res 1998;12:465–471.
32. Pessayre D, Larrey D, Funck-Brentano C, ,et al. Drug interactions and hepatitis produced by some macrolide antibiotics. J Antimicrob Chemother. 1985 ;16 Suppl A:181-94.
33. Skakun NP, Oleinik AN.Tetracycline lesions of the liver and their treatment Mater Med Pol. Vrach Delo. 1984;(11):91-95.
34. Letteron P, Fromenty B,Terris B ,et al. Acute and chronic hepatic steatosis lead to in viva lipid peroxidation in mice. Hepatology, 1996; 24: 206-208.
35. 孙创斌, 淤泽溥.去脂软肝丸对四环素致小鼠脂肪肝模型肝脂的影响. 云南中医学院学报.2002;25(1):8-10.
36. Mcclure MT, Stupans I. Investigation of the mechanism by which cyclophosphamide alters P450 in male rats. Biochem Pharmacol.1992;43:2655-2658.
37. Lear L, Nation RL, Stupans I. Effects of CP and adriamycin on rat hepatic microsomal glucuronidation and lipod peroxidation. Biochem Pharmacol. 1992;44:747-753.
38. Honjo I, Suou T, Hirayama C.Hepatotoxicity of cyclophosphamide in man: pharmacokinetic analysis.Res Commun Chem Pathol Pharmacol. 1988;61(2):149-165.
39. 施畅 , 廖明阳. 环磷酰胺与异环磷酰胺在体内的代谢特点分析. 解放军药学学报.2001;17(2):92-94.
40. Huang Q, Dunn RT, Jayadev S ,et al.Assessment of Cisplatin-Induced Nephrotoxicity by Microarray Technology.Toxicol.Sci. 2001;63:196-207.
41. 由凤秋.药物性肝损害 35 例临床分析. 陕西医学杂志.2004;11:1063-1064.
42. Hamadeh HK, Bushel PR, Jayadev S, et al. Gene Expression Analysis RevealsChemical-Specific Profiles. Toxicol. Sci. 2002;67:219-231.
43. Abelson PH.A third technological revolution.Science. 1998;279:2019.
44. Vrana KE, Freemany WM, Aschner M, , et al.Use of Microarray Technologies in Toxicology Research.NeuroToxicology 2003;24: 321–332.
45. Afshari CA, Nuwaysir EF, Barrett JC. Application of complementary DNA microarray technology to carcinogen identification, toxicology, and drug safety evaluation. Cancer Res. 1999;59(19):4759-4760.
46. Smith LL. Key challenges for toxicologists in the 21st century. Trends Pharmacol Sci. 2001;22(6): 281-285.
47. Simmons PT, Portier CJ. Toxicogenomics: the new frontier in risk analysis.Carcinogenesis. 2002; 23(6): 903-905.
48. Stears RL, Martinsky T, Schena M. Trends in microar-ray analysis. Nat Med 2003, 1(9): 140-145.
49. http://dir.niehs.nih.gov/microarray/
50. Bartosiewicz M, Trounstine M, Barker D et al. Development of a Toxicological Gene Array and Quantitative Assessment of This Technology . Arch Biochem Biophys. 2000, 376(1):66-73.
51. Yue, H. et al. An evaluation of the performance of cDNA microarrays for detecting changes in global mRNA expression. Nucleic Acids Res. 2001, 29(8):E41.
52. Brazma A, Hingamp P, Quackenbush J, et al. Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat Genet. 2001; 29(4):365-371.
53. 伍亚舟,张彦琦,黄明辉,等.基因芯片表达数据的标准化策略研究. 第三军医大学学报,2004,7:594-597.
54. 敖林,曾志雄,方志俊,等 . 小鼠毒理基因芯片的制作。癌变·畸变·突变,待发表.
55. Shioda T. Application of DNA microarray to toxicological research.. J Environ Pat hol Toxicol Oncol. 2004;23(1):13-31.
56. Robin L. Stears et al. Trends in microar-ray analysis. Nat Med 2003, 1(9): 140-145.
57. Rockett JC,Luft JC, Garges JB, et al.Development of a 950-gene DNA array for examining gene expression patterns in mouse testis.Genome Biology.2001;2(4):research0014.1–0014.9.
58. Halgren RG, Fielden MR, Fong CJ, et al.Assessment of clone identity and sequence fidelity for 1189 IMAGE cDNA clones. Nucleic Acids Res 2001;29: 582–588.
59. Yang YH, Speed T . Design issues for cDNA microarray experiments. Nat Rev Genet. 2002; 3(8):579-588.
60. Sandberg R, Yasuda R, Pankratz DG, et al.Regional and strain-specific gene expression mapping in the adult mouse brain. Proc Natl Acad Sci USA.2000. 97: 11038–11043.
61. He B, Munson AE, Meade BJ,et al.Analysis of gene expression induced by irritant and sensitizing chemicals using oligonucleotide arrays. Intern Immuno Pharmacol 2001; 1 :867–879.
62. 范保星, 孙敬芬, 刘庆峰等. 总 RNA 和 MRNA 来源的探针与 CDNA 芯片杂交的差异研究. 生物技术通讯. 2004;15(1):20-22.
63. Cox WG, Beaudet MP, Agnew JY,et al. Possible sources of dye-related signal correlation bias in two-color DNA microarray assays.Anal Biochem. 2004 Aug 15;331(2):243-54.
64. Rosenzweig BA, Pine PS, Domon OE, et al. Dye bias correction in dual-labeled cDNA microarray gene expression measurements. Environ Health Perspect. 2004;112(4):480-487.
65. Hill AA, Brown EL, Whitley MZ, et al. Evaluation of normalization procedures for oligonucleotide array data based on spiked cRNA controls. Genome Biol. 2001;2(12): RESEARCH0055.
66. 伍 亚舟 , 易 东 , 李辉 智 , 等 . 基 因表 达芯 片标 准化 研究 进展 . 数 理医药学 杂志.2005;18(1):60-63.
67. Warrington JA, Nair A, Mahadevappa M, et al. Comparison of human adult and fetal expression and identification of 535 housekeeping/maintenance genes. Physiol Genomics. 2000; 2(3): 143-147.
68. Chen H, Liu J, Merrick BA, et al. Genetic events associated with arsenic-induced malignant transformation: applications of cDNA microarray technology. Mol Carcinog. 2001;30(2):79-87.
69. 马淑华,王升启,等. cDNA 芯片技术杂交效率的优化 .药学学报,2002,37(2):153-157.
70. Wang X, Ghosh S, Guo S. Quantitative quality control in microarray image processing and data acquisition. Nucleic Acids Res. 2001;29:E75.
71. Zhou Y, Gwadry FG, Reinhold WC, et al. Transcriptional regulation of mitotic genes by camptothecin-induced DNA damage: microarray analysis of dose- and time-dependent effects. Cancer Res. 2002;62:1688-1695.
72. Kojima N, Shiojiri N, Sakai Y, et al. Expression of neuritin during liver maturation and regeneration. FEBS Lett. 2005; [Epub ahead of print]
73. Rajeevan MS, Vernon,SD, Taysavang M, et al.Validation of Array-Based Gene Expression Profiles by Real-Time (Kinetic) RT-PCR.J Mol Diag.2001;3(1):26-31.
74. Wittwer CT, Herrmann MG,Moss AA.,et.al . Rasmussen RP: Continuous. fluorescence monitoring of rapid cycle DNA amplification. Biotechniques 1997; 22:130-138.
75. Thompson KL, Afshari CA, Amin RP, et al. Identification of Platform-Independent Gene Expression Markers of Cisplatin Nephrotoxicity Environ Health Perspec .2004; 112(4): 488-494.
76. Longueville FD ,Atienzar FA, Marcq L, et al.Use of a Low-Density Microarray for Studying Gene Expression Patterns Induced by Hepatotoxicants on Primary Cultures of Rat Hepatocytes. ToxSci Advance Access .2003; 75(2):378-392.
77. Krasnova IN, Mccoy MT, Ladenteim B,et al.cDNA array analysis of gene expression profiles in the striata of wild-type and Cu/Zn superoxide dismutase transgenic mice treated with neurotoxic doses of amphetamine. J FASEB. 2002;16:1379-1388.
78. Huang Q, Jin X, Gaillard ET, et al. Gene expression profiling reveals multiple toxicity endpoints induced by hepatotoxicants. Mutat Res. 2004 ; 549(1-2):147-67.
79. Minami K, Saito T, Narahara M, et al. Relationship between hepatic gene expression profiles and hepatotoxicity in five typical hepatotoxicant-administered rats.Toxicol Sci. 2005;87(1):296-305.
80. McMillian M, Nie AY, Parker JB, et al.A gene expression signature for oxidant stress/reactive metabolites in rat liver.Biochem Pharmacol. 2004;68(11):2249-61.
81. 吴骋,贺佳,贺宪民,付旭平. cDNA 微阵列实验分析中常用的统计方法.国外医学.生物医学工程分册.2004;27(5):305-308.
82. Eisen MB,Spellman PT, et al. Cluster analysis and display of genome-wide expressionpatterns. Proc.Natl Acad Sci U S A .1998,95:14863-14868.
83. Jain AK, Murty MN, Flynn PJ, et al. Data clustering: a review. ACM Computing surveys,1999,31:264-323.
84. Dudoit S , Fridlyand J. Speed TP . Comparison of discrimination methods theclassification-Oftum usinggene expressiondata.J. Am.Stat Assoc.2002,97(457):77-87.
85. Golub TR, Slonim DK, Tamayo P, et al.Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999 ; 286(5439):531-537.
86. Mavroudi S, Papadimitriou S, Bezerianos A , et al.Gene expression data analysis with a dynamically extended self-organized map that exploits class information. Bioinformatics. 2002;18(11):1446-1453.
87. Stenven J, Bulera, Susan M, et al RNA expression in the early characterization of hepatotoxicants in Wistar rats by high-density DNA microarrays.Hepatology . 2001; 5(33):1239-1258.
88. Amacher DE, Martin BA ,et al. Tetracycline-induced steatosis in primary canine hepatocyte cultures. Fundam Appl Toxicol, 1997;40(2): 256-263.
89. Gulick T, Cresci S, Caira T,et al. The peroxisome proliferators-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci USA. 1994;91(23):11012-11016.
90. Larsson SL, Skogsberg J, Bjorkegren J ,et al. The low density lipoprotein receptor prevents secretion of dense apoB100-containing lipoproteins from the liver. J Biol Chem, 2004;279(2):831-836.
91. Letteron P, Sutton A, Mansouri A, et al. Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice. Hepatology, 2003 ,38(1):133-140.
92. Murphy EJ.Sterol carrier protein-2: not just for cholesterol any more.Mol Cell Biochem.2002 ;239(1-2):87-93.
93. Descalzi Cancedda F, Dozin B, Zerega B, et al. Extracellular fatty acid binding protein (ex-FABP) is a stress protein expressed during chondrocyte and myoblast differentiation. Osteoarthritis Cartilage, 2001;Suppl A:S118-122.
94. 王瑞石,王庆文. 药物的肝脏毒性.肾脏病与透析肾移植杂志. 2004; 5:459-462.
95. Kubota S, Kiyosawa H, Nomura Y, et al. Ornithine decarboxylase overexpression in mouse 10T1/2 fibroblasts: cellular transformation and invasion. J Natl Cancer Inst. 1997;89(8):567-71.
96. Fiebiger E, Maehr R, et al. Invariant chain controls the activity of extracellular cathepsin L J Exp Med. 2002 ;196 (9):1263-1269.
97. Newsholme EA , Parry - Billings M. Properties of glutamine release from muscle and importance for the immune system. J Parenteral Enteral Nutr , 1990 ;14 :63S - 64S.
98. 王 晓 泛素 226s 蛋白酶体途径在凋亡中的作用. 国外医学·分子生物学分册.2002;24(2):97-99.
99. Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997; 91(4):479-89.
100. Klip A,Tsakiridis T,Marette A, et al.Regulation of expression of glucose transporters by glucose:a review of studies in vivo and in cell culture.FASEB J.1994; 8:43.
101. Techel D, Hafker T,Muschner S, et al . Molecular analysis of a glucose2 regulated gene ( grp78 ) of neurospora carssa. Biochem Biophys Acta. 1998; 1397 (1) : 21-26.
102. 柏干荣,陆松敏,李萍等.失血性休克对肠上皮细胞线粒体编码的细胞色素氧化酶mRNA 表达变化的研究. 第三军医大学学报,2003;25(15):1315-1317.
103. Colletti LM , Kunkel SL. Chemokine expression dring hepatic ischemia/ reperfusion induced lung injury in the rat ,the role of epithelial neutrophil activating protein . Clin Invest .1995 ; 95 (1) :134.
104. Liu Zhongli, Han Zhengxu, Cheng P in, et al. Studies on B io2an t ioxidants. Ch in J Chem istry,1991;9 (2) : 144 151.
105. Khan S, Ramwani JJ, O'Brien PJ. Hepatocyte toxicity of mechlorethamine and other alkylating anticancer drugs. Role of lipid peroxidation. Biochem Pharmacol. 1992 ;43(9):1963-1967.
106. 施畅, 廖明阳. 环磷酰胺与异环磷酰胺致肝毒性机制的比较. 卫生毒理学杂志. 2000; 1 4(2):99-102.
107. Pari L, Murugan P. Protective role of tetrahydrocurcumin against erythromycinestolate-induced hepatotoxicity. Pharmacol Res. 2004;49(5):481-486 .
108. Chen QM, Tu VC ,et al. Apoptosis and heart failure: mechanisms and therapeutic implications. Am J Cardiovasc Drugs, 2002;2(1):43-57.
109. Tilg H , Mair J , Herold U , et al . Stress proteins and myocardial protection : is there a role for tumor necrosis factor ? Lancet ,1991 ;337 : 677.
110. Robin M2A , Le Roy M , Descatoire V , et al . Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug induced hepatitis. J Hepatol ,1997 ;26 :Suppl 1 :23.
111. 王水明,刘友生,陈锐.严重缺氧后心肌细胞损害敏感性的分子机制. 中华烧伤杂志.2003; 19 (3) : 134-136.
112. 李永旺,麻莉,毛宝龄,等. 内毒素诱导的 TLR4-MD2 信号传导通路. 中国药理学通报.2002;18 (2) :121.
113. Hennet T, Chui D, Paulson JC, Marth JD.Immune regulation by the ST6Gal sialyltransferase. Proc Natl Acad Sci U S A. 1998;95(8):4504-4509.
114. Pongracz P, Altbacker V.The effect of early handling is dependent upon the state of the rabbit (Oryctolagus cuniculus) pups around nursing.Dev Psychobiol. 1999;35(3):241-251.
115. Watanabe S, Ishida S, Koike K, Arai K.Characterization of cis-regulatory elements of the c-myc promoter responding to human GM-CSF or mouse interleukin 3 in mouse proB cell line BA/F3 cells expressing the human GM-CSF receptor.Mol Biol Cell. 1995;6(6):627-636.
116. Sitrin RG.纤维蛋白原对单核巨噬细胞 NF-κB 转录因子的激活作用. 国外医学·分子生物学分册.21(6):379.
117. Muzio M , N i J , Fen G P, et al. IRAK (pelle) family member IRAK2 and M yD88 as proximalmediators of IL-1 signaling . Science, 1997, 278.
118. Deng C, Radu C, Diab A, et al.IL-1 receptor-associated kinase 1 regulates susceptibility to organ-specific autoimmunity.J Immunol. 2003 ;170(6):2833-2842.
119. Huang Y, Krein PM, et al. Complement factor B gene regulation: synergistic effects of TNF-alpha and IFN-gamma in macrophages. [J]. J Immunol. 2002 ,169(5):2627-35.
120. Matsumoto M, Fukuda W, Circolo A, et al. Abrogation of the alternative complementpathway by targeted deletion of murine factor B. Proc Natl Acad Sci U S A. 1997;94(16):8720-8725.
121. Halonen SK, Taylor GA, Weiss LM et al.Gamma interferon-induced inhibition of Toxoplasma gondii in astrocytes is mediated by IGTP.Infect Immun. 2001;69 (9):5573-5576.
122. Zhang HM, Yuan J, Cheung P et al.Overexpression of interferon-gamma-inducible GTPase inhibits coxsackievirus B3-induced apoptosis through the activation of the phosphatidylinositol 3-kinase/Akt pathway and inhibition of viral replication. Biol Chem. 2003;278(35):33011-33019.
123. Mistry MJ,Clay MA ,Kelly ME et al. Apolipoprotein E restricts interleukin-dependent T lymphocyte proliferation at the G1A/G1B boundary. Cell Immunol,1995;162(1):14-23.
124. Browning PJ,Robert DD,Zabrenetzky V et al. Apolipoprotein E (ApoE), a novel heparin-binding protein inhibits the development of Kaposi's sarcoma-like lesions in BALB/c nu/nu mice. J Exp Med,1994;180(5):1949-1954.
125. Neve BP,Corseaux D ,Chinetti G, et al. PPARαagonists inhibit tissue factor expression in human monocytes and macrophages. Circulation .2001;103 :207-212.
126. Delerive P, Martin NF ,Chinetti G, et al. PPAR activators inhibit thrombin induced endothelin1 production in human vascular endothelial cells byinhibiting the AP-1 signalling pathway. Circ Res .1999 ;85 : 394-402.
127. 刘树人.钙-钙调蛋白拮抗剂对肝细胞损伤的预防作用. 国外医学.消化系疾病分册.1995,15(2):98-100.
128. Camacho P, Lechleiter JD.Calreticulin inhibits repetitive intracellular Ca2+ waves. Cell .1995 ;82∶765-771.
129. Dowd DR ,MacDonald PN ,Komm BS ,et al Evidence for early induction of calmodulin gene expression in lymphocytes under going glucocorticoid2mediated apoptosis1. J Bio Chem. 1991 ; 266 :18423.
130. Moore J D. The RAN-GTPase and cell-cycle control. Biocssays.2001.23:77-85.
131. 管 睿 崔 英 . rab 家 族 及 其 在 囊 泡 运 输 中 的 作 用 . 国 外 医 学 . 遗 传 学 分册.2005;28(2):91-93.
132. Sordella R, Classon M, Hu KQ, et al. Modulation of CREB activity by the RhoGTPase regulates cell and organism size during mouse embryonic development.Dev Cell. 2002 ;2(5):553-565.
133. Sordella R, Jiang W, Chen GC, et al Modulation of Rho GTPase signaling regulates a switch between adipogenesis and myogenesis.Cell. 2003 Apr 18;113(2):147-58.
134. Kim SW, Hayashi M, Lo JF, et al. ADP-ribosylation factor 4 small GTPase mediates epidermal growth factor receptor-dependent phospholipase D2 activation.J Biol Chem. 2003 ; 278(4):2661-8.
135. Trougakos IP, So A, Jansen B,et al. Silencing expression of the clusterin/apolipoprotein j gene in human cancer cells using small interfering RNA induces spontaneous apoptosis, reduced growth ability, and cell sensitization to genotoxic and oxidative stress. Cancer Res. 2004 ;64(5):1834-1842.
136. Wu X ,Rubin M , Fan Z ,et al. Involvement of p27 KIP1 in G1 arrest mediated by an antiepidermal growth factor receptor monoclonal antibody. Oncogene..1996 ;12 :1397 – 1403.
137. Bordeaux MC, Farcet C, Granger L, et al. The RET proto-oncogene induces apoptosis: a novel Mechanism for Hirschsprung disease. EMBO J 2000;19:4056-4063.
138. Li C ,Hampson IN ,Hampson L , et al . CD105 antagonizes the inhibitory signaling of transforming growth factor betal on human vascular endothelial cells. FASEB J , 2000 ,14(1) :55 - 64.
139. 高晓东. 沈志祥.转化生长因子 β 与细胞凋亡.国外医学.输血及血液学分册.2004;27(1):30-33.
140. Ruckdeschel K, Mannel O, Schrottner P.Divergence of apoptosis-inducing and preventing signals in bacteria-faced macrophages through myeloid differentiation factor 88 and IL-1 receptor-associated kinase members.J Immunol. 2002;168(9):4601-4611.
141. Mayo MW, Wang CY, Cogswell PC , et al. Requirement of NF-κB activation to supress P53 - independent apoptosis induced by oncogenic Ras. Science . 1997 ; 278 :1812.
142. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. Opposingeffects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995;270:1326-1331.
143. New L, Jiang Y, Zhao M et al. PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J, 1998, 17 (12): 3372-3384.
144. 方希敏. 陈铭珍. 陈日玲.细胞色素 c 与凋亡的研究进展 国外医学.输血及血液学分册 2004;27(5):420-422.
145. Okamoto K ,Prives C. A role if cyclin G in the process of apoptosis. Oncogene,1999,18(32):4604-4615.
146. Morita N,Kiryu S,Kiyama H.p53-independent cyclin G expression in a group of mature neurons and its enhanced expression during nerve regeneration. J Nertosci.1996,16(19):5961-5966.
147. Mbebi C,See V, Mereken L, et al. Amyloid precursor protein family induced neuronal death is mediated by impairment of the neuropretecsive calcium/calmodulin protein kinase Ⅳ-dependent signaling pathway. J Biol Chem, 2002,277(23):20979-20990.
148. Loo DT , Copani AG, et al. Apoptosis is induced byβ2amyloid in culture central nervous system neurons. Proc Natl Acad Sci.1993;90 :7951-7955.
149. Wakasugi M, Kawashima A, Morioka H,et al. DDB accumulates at DNA damage sitesimmediately after uv irradiation and directly stimulates nucleotideexcision repair. J Biol Chem 2002;277:1637-1640.
150. Diehl JA, Yang W, Rimerman RA, et al .Hsc70 regulates accumulation of cyclin D1 and cyclin D1-dependent protein kinase.Mol Cell Biol. 2003;23(5):1764-1774.
151. Chen YC , Lin2Shiau SY, Lin JK, et al . Involvement of heat shock protein 70 and p53 proteins in attenuation of UVC induced apoptosis by thermal stress in hepatocellular carcinoma cells. Photochem Photobiol . 1999 ;70 :78-86.
152. Bose J, Gruber AD, Helming L, et al . The phosphatidylserine receptor has essential functions during embryogenesis but not in apoptotic cell removal.J Biol. 2004;3(4):15.
153. Lockhart AC, Tirona RG,Kim RB. Pharmacogenetics of ATP-binding cassette transporters in cancer and chemotherapy. Mol Cancer Ther, 2003,2(7): 685-698.
154. van der Kolk DM, Vellenga E , Muller M, et al . Multidrug resistance protein MRP1 , glutathione , and related enzymes , their importance in acute myloid leukemia . Adv Exp Med Biol ,1999 ;457 :187-198.
155. Wu L, Gu J, Weng Y, Kluetzman K, et al . Conditional knockout of the mouseNADPH-cytochrome p450 reductase gene.Genesis. 2003 ;36(4):177-81.
156. 于建洋,窦华林.头孢菌素类药物“双硫醒”样反应 52 例临床分析. 临床医学.2004;6:3.
157. Meech R , Mackenzie PI . Structure and function of uridine diphosphate glucuronosyltransferases . Clin Exp Pharmacol Physiol . 1 9 9 7 , 2 4 ( 1 2 ) : 9 0 7 - 9 1 5 .
158. 莫隽全,区庆嘉,何劲松. 小鼠 UGT1A1mRNA 在慢性肝损伤时的表达. 中国普通外科杂志.2003;12(4):276-279.
159. 卢洁玲.药物的不良反应.上海医药;1998;19(10):37-38.
160. Cao Jia, et al. Toxicogenomics and application and DNA microarrays. Chinese Journal of Pharmacology and Toxicology, 2000,14(5):336-340.
1. Vrana KE, Freeman WM, Aschner M. Use of microarray technologies in toxicology research [J]. Neurotoxicology. 2003, 24(3): 321-332.
2. Anderson NL,Matheson AD,Steiner S. Proteomics:applications in basic and applied biology [J]. Curr Opin Biotechnol. 2000 ,11(4 ): 408-412.
3. Huang J , Lih CJ, et al. Global analysis of growth phase responsive gene expression and regulation of antibiotic biosynthetic pathways in Streptomyces coelicolor using DNA microarrays [J]. Genes & development. 2001, 15 (23): 3183-3192.
4. Halgren RG, Fielden MR, Fong CJ, et al. Assessment of clone identity and sequence fidelity for 1189 IMAGE cDNA clones [J]. Nucleic Acids Res 2001, 29 (2): 582–588.
5. Lipshutz R, Fodor S ,Gingeras T, et al. High desity synthetic oligonucleotide arrays[J].Nature Gentics supplement. 1999,21(3): 20-24.
6. Shioda T. Application of DNA microarray to toxicological research [J]. J Environ Pathol Toxicol Oncol. 2004,23(1):13-31.
7. Robin L. Stears et al. Trends in microarray analysis [J]. Nat Med 2003, 1(9): 140-145.
8. Yang YH, Speed T . Design issues for cDNA microarray experiments [J] . Nat Rev Genet. 2002, 3(8):579-588.
9. Lee ML, Kuo FC, Whitmore GA, et al. Importance of replication in microarray gene expression studies: statistical methods and evidence from repetitive cDNA hybridizations.[J] Proc Natl Acad Sci U S A. 2000, 97(18):9834-9839.
10. Tilstone C. DNA microarrays: Vital statistics [J]. Nature 2003 , 424(6949): 610-612.
11. Bartosiewicz M, Trounstine M, Barker D et al. Development of a Toxicological Gene Array and Quantitative Assessment of This Technology [J]. Arch Biochem Biophys. 2000, 376(1):66-73.
12. Yue, H. et al. An evaluation of the performance of cDNA microarrays for detecting changes in global mRNA expression [J]. Nucleic Acids Res. 2001, 29(8):E41.
13. Brown C S, Goodwin P C, Sorgor P K . Image metrics in the statistical analysis of DNA microarray dat . [J]. Proc Natl Acad Sci U S A. 2001,98(16) :8944-8949.
14. Yang YH, Dudoit S, Luu P, et al. Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation [J]. Nucleic acids research. 2002, 30(4): E15.
15. Ideker T, Thorsson V, et al. Testing for differentially-expressed genes by maximum-likelihood analysis of microarray data [J]. J Comput Biol .2000, 7 (6) :805-817 .
16. Draghici S. Statistical intelligence: effective analysis of highdensity microarray data [J].Drug Discov Today 2002, 7 (11 Suppl): S55–S63.
17. Alon U, Barkai N, Notterman DA, et al. Broad patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays [J]. Proc Natl Acad Sci U S A. 1999, 96 (12): 6745–6750.
18. Zhou X , Kao MC, Wong WH . Transitive functional annotation by shortest-path anal-ysis of gen expression data [J]. Proc Natl Acad Sci U S A..2002,99 (20):12783-12788.
19. Brazma A, Hingamp P, Quackenbush J, et al Minimum information about a microarray experiment (MIAME)-toward standards for microarray data [J]. Nat Genet.2001 , 29(4):365-371.
2. WHO 国际药物监测合作计划发展概况 药物不良反应杂志 1999;1:47 .
3. Farr S, Dunn RT. Concise review:gene expression applied to toxicology. Toxicol Sci. 1999;50(1):1-9.
4. Corton JC, Stauber AJ. et al. Toward construction of a transcript profile database predictive of chemical toxicity. Toxicol Sci. 2000;58(2):217-219.
5. Nuwaysir EF, Bittner M, Trent J, et al. Microarrays and toxicology: the advent of toxicogenomics. Mol Carcinog. 1999;24(3):153-159.
6. 陈小朋编译. 基因组学及相关组学技术对药物毒理学的影响. 国外医学药学分册.2002;29(5):261-264.
7. Hamadeh HK, Bushel PR, Jayadev S, et al. Prediction of Compound Signature Using High Density Gene Expression Profiling. Toxicol Sci, 2002;67:232-240.
8. Lu AY. Drug metabolism research challenges in the new millennium. Drug Metab Dispos. 1998;26(12):1217-1222.
9. Hirvonen A. Polymorphisms of xenobiotic metabolizing enzymes and susceptibility to cancer. Environ Health Perspect. 1999;107(Suppl):37-47.
10. Mc Carthy JJ, Hilfiker R. The use of single nucleotide polymorphism maps in pharmacogenomics. Nat Biotechnol,2 000; 8∶505-508.
11. Ganter B, Tugendreich S, Pearson CI,et al. Development of a large-scale chemogenomics database to improve drug candidate selection and to understand mechanisms of chemical toxicity and action.J Biotechnol. 2005; 119(3):219-244.
12. Baker TK, Carfagna MA, Gao H ,et al. Temporal gene expression analysis of monolayer cultured rat hepatocytes. Chem Res Toxicol. 2001;14: 1218-1231.
13. Mattes WB, Pettit SD, Sansone SA, et al. Database Development in Toxicogenomics: Issues and Efforts.Environ Health Perspect. 2004;112(4):495-505.
14. Waring JF, Jolly RA, Ciurlionis R, et al .Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles. Toxicol. Appl. Pharmacol. 2001; 175 :28–42.
15. Steiner G, Suter L, Boess F, et al .Discriminating different classes of toxicants by transcript profiling,.Environ. Health Perspect. 2004; 112: 1236–1248.
16. Freeman K. Toxicogenomics data: the road to acceptance. Environ.Health Perspect. 2004; 112 :A678–A685.
17. Morgan KT, Jayyosi Z, Hower MA, et al .The hepatic transcriptome as a window on whole-body physiology and pathophysiology. Toxicol Pathol. 2005;33(1):136-145.
18. Larrey D.Epidemiology and individual susceptibility to adverse drug reactions afecting the liver.Seminars in liver Disease.2002;22(2):145-55.
19. Lewis JH, Zimmerman HJ. Drug-induced liver disease. Med Clin North Am. 1989 ;73(4):775-792.
20. Ostapowicz G,Fontana RJ,Larson AM,et a1.Etiology and outcome of acute liver failure in the USA : preliminary results of prospective multicenter study.Hepatology.1999; 30:221 A.
21. Larry D. Drug-induced liver disease.J Hepatol 2000; 32:77-88.
22. Jaeschke H, Gores GJ, Cederbaum AI, et al.Mechanisms of hepatotoxicity. Toxicol Sci. 2002;65(2):166-176.
23. Maddrey WC.Drug-induced hepatotoxicity: 2005. J Clin Gastroenterol. 2005 ;39(4 Suppl 2):S83-89.
24. Gerhold D,Lu M, Xu J, et al.Monitoring expression of genes involved in drug metabolism and toxicology using DNA microarrays. Physiol Genomics.2001;5: 161–170.
25. Reilly T.P, Bourd M, Brady JN, et al. Expression profiling of acetaminophen liver toxicity in mice using microarray technology. Biochem. Biophys. Res. Commun. 2001;282:321–328.
26. Waring JF, Ciurlionis R, Jolly RA,et al. Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity, Toxicol. Lett. 2001;120:359–368.
27. Bulera SJ,.Eddy SM, Ferguson E, et al.RNA expression in the early characterization of hepatotoxicants in Wistar rats by high-density DNA microarrays, Hepatology 2001;33:1239–1258.
28. Thomas RS, Rank DR, Penn SG, et al Identification of toxicologically predictive genesets using cDNA microarrays, Mol. Pharmacol. 2001;60: 1189–1194.
29. Amacher DE, Schomaker SJ, Retsema JA. Comparison of the effects of the new azalide antibiotic azithromycin and erythromycin estolate on liver cytochrome P.450. J Antimicrob Chemother.1991;35(6):1186–1190.
30. Carevic O, Prpic V, Sverko V. Correlation between erythromycin and acid phosphatase in mouse liver. Biochim Biophys Acta. 1975;381(2):269-277.
31. Venkateswaran S, Pari L, Viswanathan P. Antiperoxidative effect of Livex, a herbal formulation against erythromycin estolate induced lipid peroxidation in rats. Phytother Res 1998;12:465–471.
32. Pessayre D, Larrey D, Funck-Brentano C, ,et al. Drug interactions and hepatitis produced by some macrolide antibiotics. J Antimicrob Chemother. 1985 ;16 Suppl A:181-94.
33. Skakun NP, Oleinik AN.Tetracycline lesions of the liver and their treatment Mater Med Pol. Vrach Delo. 1984;(11):91-95.
34. Letteron P, Fromenty B,Terris B ,et al. Acute and chronic hepatic steatosis lead to in viva lipid peroxidation in mice. Hepatology, 1996; 24: 206-208.
35. 孙创斌, 淤泽溥.去脂软肝丸对四环素致小鼠脂肪肝模型肝脂的影响. 云南中医学院学报.2002;25(1):8-10.
36. Mcclure MT, Stupans I. Investigation of the mechanism by which cyclophosphamide alters P450 in male rats. Biochem Pharmacol.1992;43:2655-2658.
37. Lear L, Nation RL, Stupans I. Effects of CP and adriamycin on rat hepatic microsomal glucuronidation and lipod peroxidation. Biochem Pharmacol. 1992;44:747-753.
38. Honjo I, Suou T, Hirayama C.Hepatotoxicity of cyclophosphamide in man: pharmacokinetic analysis.Res Commun Chem Pathol Pharmacol. 1988;61(2):149-165.
39. 施畅 , 廖明阳. 环磷酰胺与异环磷酰胺在体内的代谢特点分析. 解放军药学学报.2001;17(2):92-94.
40. Huang Q, Dunn RT, Jayadev S ,et al.Assessment of Cisplatin-Induced Nephrotoxicity by Microarray Technology.Toxicol.Sci. 2001;63:196-207.
41. 由凤秋.药物性肝损害 35 例临床分析. 陕西医学杂志.2004;11:1063-1064.
42. Hamadeh HK, Bushel PR, Jayadev S, et al. Gene Expression Analysis RevealsChemical-Specific Profiles. Toxicol. Sci. 2002;67:219-231.
43. Abelson PH.A third technological revolution.Science. 1998;279:2019.
44. Vrana KE, Freemany WM, Aschner M, , et al.Use of Microarray Technologies in Toxicology Research.NeuroToxicology 2003;24: 321–332.
45. Afshari CA, Nuwaysir EF, Barrett JC. Application of complementary DNA microarray technology to carcinogen identification, toxicology, and drug safety evaluation. Cancer Res. 1999;59(19):4759-4760.
46. Smith LL. Key challenges for toxicologists in the 21st century. Trends Pharmacol Sci. 2001;22(6): 281-285.
47. Simmons PT, Portier CJ. Toxicogenomics: the new frontier in risk analysis.Carcinogenesis. 2002; 23(6): 903-905.
48. Stears RL, Martinsky T, Schena M. Trends in microar-ray analysis. Nat Med 2003, 1(9): 140-145.
49. http://dir.niehs.nih.gov/microarray/
50. Bartosiewicz M, Trounstine M, Barker D et al. Development of a Toxicological Gene Array and Quantitative Assessment of This Technology . Arch Biochem Biophys. 2000, 376(1):66-73.
51. Yue, H. et al. An evaluation of the performance of cDNA microarrays for detecting changes in global mRNA expression. Nucleic Acids Res. 2001, 29(8):E41.
52. Brazma A, Hingamp P, Quackenbush J, et al. Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat Genet. 2001; 29(4):365-371.
53. 伍亚舟,张彦琦,黄明辉,等.基因芯片表达数据的标准化策略研究. 第三军医大学学报,2004,7:594-597.
54. 敖林,曾志雄,方志俊,等 . 小鼠毒理基因芯片的制作。癌变·畸变·突变,待发表.
55. Shioda T. Application of DNA microarray to toxicological research.. J Environ Pat hol Toxicol Oncol. 2004;23(1):13-31.
56. Robin L. Stears et al. Trends in microar-ray analysis. Nat Med 2003, 1(9): 140-145.
57. Rockett JC,Luft JC, Garges JB, et al.Development of a 950-gene DNA array for examining gene expression patterns in mouse testis.Genome Biology.2001;2(4):research0014.1–0014.9.
58. Halgren RG, Fielden MR, Fong CJ, et al.Assessment of clone identity and sequence fidelity for 1189 IMAGE cDNA clones. Nucleic Acids Res 2001;29: 582–588.
59. Yang YH, Speed T . Design issues for cDNA microarray experiments. Nat Rev Genet. 2002; 3(8):579-588.
60. Sandberg R, Yasuda R, Pankratz DG, et al.Regional and strain-specific gene expression mapping in the adult mouse brain. Proc Natl Acad Sci USA.2000. 97: 11038–11043.
61. He B, Munson AE, Meade BJ,et al.Analysis of gene expression induced by irritant and sensitizing chemicals using oligonucleotide arrays. Intern Immuno Pharmacol 2001; 1 :867–879.
62. 范保星, 孙敬芬, 刘庆峰等. 总 RNA 和 MRNA 来源的探针与 CDNA 芯片杂交的差异研究. 生物技术通讯. 2004;15(1):20-22.
63. Cox WG, Beaudet MP, Agnew JY,et al. Possible sources of dye-related signal correlation bias in two-color DNA microarray assays.Anal Biochem. 2004 Aug 15;331(2):243-54.
64. Rosenzweig BA, Pine PS, Domon OE, et al. Dye bias correction in dual-labeled cDNA microarray gene expression measurements. Environ Health Perspect. 2004;112(4):480-487.
65. Hill AA, Brown EL, Whitley MZ, et al. Evaluation of normalization procedures for oligonucleotide array data based on spiked cRNA controls. Genome Biol. 2001;2(12): RESEARCH0055.
66. 伍 亚舟 , 易 东 , 李辉 智 , 等 . 基 因表 达芯 片标 准化 研究 进展 . 数 理医药学 杂志.2005;18(1):60-63.
67. Warrington JA, Nair A, Mahadevappa M, et al. Comparison of human adult and fetal expression and identification of 535 housekeeping/maintenance genes. Physiol Genomics. 2000; 2(3): 143-147.
68. Chen H, Liu J, Merrick BA, et al. Genetic events associated with arsenic-induced malignant transformation: applications of cDNA microarray technology. Mol Carcinog. 2001;30(2):79-87.
69. 马淑华,王升启,等. cDNA 芯片技术杂交效率的优化 .药学学报,2002,37(2):153-157.
70. Wang X, Ghosh S, Guo S. Quantitative quality control in microarray image processing and data acquisition. Nucleic Acids Res. 2001;29:E75.
71. Zhou Y, Gwadry FG, Reinhold WC, et al. Transcriptional regulation of mitotic genes by camptothecin-induced DNA damage: microarray analysis of dose- and time-dependent effects. Cancer Res. 2002;62:1688-1695.
72. Kojima N, Shiojiri N, Sakai Y, et al. Expression of neuritin during liver maturation and regeneration. FEBS Lett. 2005; [Epub ahead of print]
73. Rajeevan MS, Vernon,SD, Taysavang M, et al.Validation of Array-Based Gene Expression Profiles by Real-Time (Kinetic) RT-PCR.J Mol Diag.2001;3(1):26-31.
74. Wittwer CT, Herrmann MG,Moss AA.,et.al . Rasmussen RP: Continuous. fluorescence monitoring of rapid cycle DNA amplification. Biotechniques 1997; 22:130-138.
75. Thompson KL, Afshari CA, Amin RP, et al. Identification of Platform-Independent Gene Expression Markers of Cisplatin Nephrotoxicity Environ Health Perspec .2004; 112(4): 488-494.
76. Longueville FD ,Atienzar FA, Marcq L, et al.Use of a Low-Density Microarray for Studying Gene Expression Patterns Induced by Hepatotoxicants on Primary Cultures of Rat Hepatocytes. ToxSci Advance Access .2003; 75(2):378-392.
77. Krasnova IN, Mccoy MT, Ladenteim B,et al.cDNA array analysis of gene expression profiles in the striata of wild-type and Cu/Zn superoxide dismutase transgenic mice treated with neurotoxic doses of amphetamine. J FASEB. 2002;16:1379-1388.
78. Huang Q, Jin X, Gaillard ET, et al. Gene expression profiling reveals multiple toxicity endpoints induced by hepatotoxicants. Mutat Res. 2004 ; 549(1-2):147-67.
79. Minami K, Saito T, Narahara M, et al. Relationship between hepatic gene expression profiles and hepatotoxicity in five typical hepatotoxicant-administered rats.Toxicol Sci. 2005;87(1):296-305.
80. McMillian M, Nie AY, Parker JB, et al.A gene expression signature for oxidant stress/reactive metabolites in rat liver.Biochem Pharmacol. 2004;68(11):2249-61.
81. 吴骋,贺佳,贺宪民,付旭平. cDNA 微阵列实验分析中常用的统计方法.国外医学.生物医学工程分册.2004;27(5):305-308.
82. Eisen MB,Spellman PT, et al. Cluster analysis and display of genome-wide expressionpatterns. Proc.Natl Acad Sci U S A .1998,95:14863-14868.
83. Jain AK, Murty MN, Flynn PJ, et al. Data clustering: a review. ACM Computing surveys,1999,31:264-323.
84. Dudoit S , Fridlyand J. Speed TP . Comparison of discrimination methods theclassification-Oftum usinggene expressiondata.J. Am.Stat Assoc.2002,97(457):77-87.
85. Golub TR, Slonim DK, Tamayo P, et al.Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999 ; 286(5439):531-537.
86. Mavroudi S, Papadimitriou S, Bezerianos A , et al.Gene expression data analysis with a dynamically extended self-organized map that exploits class information. Bioinformatics. 2002;18(11):1446-1453.
87. Stenven J, Bulera, Susan M, et al RNA expression in the early characterization of hepatotoxicants in Wistar rats by high-density DNA microarrays.Hepatology . 2001; 5(33):1239-1258.
88. Amacher DE, Martin BA ,et al. Tetracycline-induced steatosis in primary canine hepatocyte cultures. Fundam Appl Toxicol, 1997;40(2): 256-263.
89. Gulick T, Cresci S, Caira T,et al. The peroxisome proliferators-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci USA. 1994;91(23):11012-11016.
90. Larsson SL, Skogsberg J, Bjorkegren J ,et al. The low density lipoprotein receptor prevents secretion of dense apoB100-containing lipoproteins from the liver. J Biol Chem, 2004;279(2):831-836.
91. Letteron P, Sutton A, Mansouri A, et al. Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice. Hepatology, 2003 ,38(1):133-140.
92. Murphy EJ.Sterol carrier protein-2: not just for cholesterol any more.Mol Cell Biochem.2002 ;239(1-2):87-93.
93. Descalzi Cancedda F, Dozin B, Zerega B, et al. Extracellular fatty acid binding protein (ex-FABP) is a stress protein expressed during chondrocyte and myoblast differentiation. Osteoarthritis Cartilage, 2001;Suppl A:S118-122.
94. 王瑞石,王庆文. 药物的肝脏毒性.肾脏病与透析肾移植杂志. 2004; 5:459-462.
95. Kubota S, Kiyosawa H, Nomura Y, et al. Ornithine decarboxylase overexpression in mouse 10T1/2 fibroblasts: cellular transformation and invasion. J Natl Cancer Inst. 1997;89(8):567-71.
96. Fiebiger E, Maehr R, et al. Invariant chain controls the activity of extracellular cathepsin L J Exp Med. 2002 ;196 (9):1263-1269.
97. Newsholme EA , Parry - Billings M. Properties of glutamine release from muscle and importance for the immune system. J Parenteral Enteral Nutr , 1990 ;14 :63S - 64S.
98. 王 晓 泛素 226s 蛋白酶体途径在凋亡中的作用. 国外医学·分子生物学分册.2002;24(2):97-99.
99. Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997; 91(4):479-89.
100. Klip A,Tsakiridis T,Marette A, et al.Regulation of expression of glucose transporters by glucose:a review of studies in vivo and in cell culture.FASEB J.1994; 8:43.
101. Techel D, Hafker T,Muschner S, et al . Molecular analysis of a glucose2 regulated gene ( grp78 ) of neurospora carssa. Biochem Biophys Acta. 1998; 1397 (1) : 21-26.
102. 柏干荣,陆松敏,李萍等.失血性休克对肠上皮细胞线粒体编码的细胞色素氧化酶mRNA 表达变化的研究. 第三军医大学学报,2003;25(15):1315-1317.
103. Colletti LM , Kunkel SL. Chemokine expression dring hepatic ischemia/ reperfusion induced lung injury in the rat ,the role of epithelial neutrophil activating protein . Clin Invest .1995 ; 95 (1) :134.
104. Liu Zhongli, Han Zhengxu, Cheng P in, et al. Studies on B io2an t ioxidants. Ch in J Chem istry,1991;9 (2) : 144 151.
105. Khan S, Ramwani JJ, O'Brien PJ. Hepatocyte toxicity of mechlorethamine and other alkylating anticancer drugs. Role of lipid peroxidation. Biochem Pharmacol. 1992 ;43(9):1963-1967.
106. 施畅, 廖明阳. 环磷酰胺与异环磷酰胺致肝毒性机制的比较. 卫生毒理学杂志. 2000; 1 4(2):99-102.
107. Pari L, Murugan P. Protective role of tetrahydrocurcumin against erythromycinestolate-induced hepatotoxicity. Pharmacol Res. 2004;49(5):481-486 .
108. Chen QM, Tu VC ,et al. Apoptosis and heart failure: mechanisms and therapeutic implications. Am J Cardiovasc Drugs, 2002;2(1):43-57.
109. Tilg H , Mair J , Herold U , et al . Stress proteins and myocardial protection : is there a role for tumor necrosis factor ? Lancet ,1991 ;337 : 677.
110. Robin M2A , Le Roy M , Descatoire V , et al . Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug induced hepatitis. J Hepatol ,1997 ;26 :Suppl 1 :23.
111. 王水明,刘友生,陈锐.严重缺氧后心肌细胞损害敏感性的分子机制. 中华烧伤杂志.2003; 19 (3) : 134-136.
112. 李永旺,麻莉,毛宝龄,等. 内毒素诱导的 TLR4-MD2 信号传导通路. 中国药理学通报.2002;18 (2) :121.
113. Hennet T, Chui D, Paulson JC, Marth JD.Immune regulation by the ST6Gal sialyltransferase. Proc Natl Acad Sci U S A. 1998;95(8):4504-4509.
114. Pongracz P, Altbacker V.The effect of early handling is dependent upon the state of the rabbit (Oryctolagus cuniculus) pups around nursing.Dev Psychobiol. 1999;35(3):241-251.
115. Watanabe S, Ishida S, Koike K, Arai K.Characterization of cis-regulatory elements of the c-myc promoter responding to human GM-CSF or mouse interleukin 3 in mouse proB cell line BA/F3 cells expressing the human GM-CSF receptor.Mol Biol Cell. 1995;6(6):627-636.
116. Sitrin RG.纤维蛋白原对单核巨噬细胞 NF-κB 转录因子的激活作用. 国外医学·分子生物学分册.21(6):379.
117. Muzio M , N i J , Fen G P, et al. IRAK (pelle) family member IRAK2 and M yD88 as proximalmediators of IL-1 signaling . Science, 1997, 278.
118. Deng C, Radu C, Diab A, et al.IL-1 receptor-associated kinase 1 regulates susceptibility to organ-specific autoimmunity.J Immunol. 2003 ;170(6):2833-2842.
119. Huang Y, Krein PM, et al. Complement factor B gene regulation: synergistic effects of TNF-alpha and IFN-gamma in macrophages. [J]. J Immunol. 2002 ,169(5):2627-35.
120. Matsumoto M, Fukuda W, Circolo A, et al. Abrogation of the alternative complementpathway by targeted deletion of murine factor B. Proc Natl Acad Sci U S A. 1997;94(16):8720-8725.
121. Halonen SK, Taylor GA, Weiss LM et al.Gamma interferon-induced inhibition of Toxoplasma gondii in astrocytes is mediated by IGTP.Infect Immun. 2001;69 (9):5573-5576.
122. Zhang HM, Yuan J, Cheung P et al.Overexpression of interferon-gamma-inducible GTPase inhibits coxsackievirus B3-induced apoptosis through the activation of the phosphatidylinositol 3-kinase/Akt pathway and inhibition of viral replication. Biol Chem. 2003;278(35):33011-33019.
123. Mistry MJ,Clay MA ,Kelly ME et al. Apolipoprotein E restricts interleukin-dependent T lymphocyte proliferation at the G1A/G1B boundary. Cell Immunol,1995;162(1):14-23.
124. Browning PJ,Robert DD,Zabrenetzky V et al. Apolipoprotein E (ApoE), a novel heparin-binding protein inhibits the development of Kaposi's sarcoma-like lesions in BALB/c nu/nu mice. J Exp Med,1994;180(5):1949-1954.
125. Neve BP,Corseaux D ,Chinetti G, et al. PPARαagonists inhibit tissue factor expression in human monocytes and macrophages. Circulation .2001;103 :207-212.
126. Delerive P, Martin NF ,Chinetti G, et al. PPAR activators inhibit thrombin induced endothelin1 production in human vascular endothelial cells byinhibiting the AP-1 signalling pathway. Circ Res .1999 ;85 : 394-402.
127. 刘树人.钙-钙调蛋白拮抗剂对肝细胞损伤的预防作用. 国外医学.消化系疾病分册.1995,15(2):98-100.
128. Camacho P, Lechleiter JD.Calreticulin inhibits repetitive intracellular Ca2+ waves. Cell .1995 ;82∶765-771.
129. Dowd DR ,MacDonald PN ,Komm BS ,et al Evidence for early induction of calmodulin gene expression in lymphocytes under going glucocorticoid2mediated apoptosis1. J Bio Chem. 1991 ; 266 :18423.
130. Moore J D. The RAN-GTPase and cell-cycle control. Biocssays.2001.23:77-85.
131. 管 睿 崔 英 . rab 家 族 及 其 在 囊 泡 运 输 中 的 作 用 . 国 外 医 学 . 遗 传 学 分册.2005;28(2):91-93.
132. Sordella R, Classon M, Hu KQ, et al. Modulation of CREB activity by the RhoGTPase regulates cell and organism size during mouse embryonic development.Dev Cell. 2002 ;2(5):553-565.
133. Sordella R, Jiang W, Chen GC, et al Modulation of Rho GTPase signaling regulates a switch between adipogenesis and myogenesis.Cell. 2003 Apr 18;113(2):147-58.
134. Kim SW, Hayashi M, Lo JF, et al. ADP-ribosylation factor 4 small GTPase mediates epidermal growth factor receptor-dependent phospholipase D2 activation.J Biol Chem. 2003 ; 278(4):2661-8.
135. Trougakos IP, So A, Jansen B,et al. Silencing expression of the clusterin/apolipoprotein j gene in human cancer cells using small interfering RNA induces spontaneous apoptosis, reduced growth ability, and cell sensitization to genotoxic and oxidative stress. Cancer Res. 2004 ;64(5):1834-1842.
136. Wu X ,Rubin M , Fan Z ,et al. Involvement of p27 KIP1 in G1 arrest mediated by an antiepidermal growth factor receptor monoclonal antibody. Oncogene..1996 ;12 :1397 – 1403.
137. Bordeaux MC, Farcet C, Granger L, et al. The RET proto-oncogene induces apoptosis: a novel Mechanism for Hirschsprung disease. EMBO J 2000;19:4056-4063.
138. Li C ,Hampson IN ,Hampson L , et al . CD105 antagonizes the inhibitory signaling of transforming growth factor betal on human vascular endothelial cells. FASEB J , 2000 ,14(1) :55 - 64.
139. 高晓东. 沈志祥.转化生长因子 β 与细胞凋亡.国外医学.输血及血液学分册.2004;27(1):30-33.
140. Ruckdeschel K, Mannel O, Schrottner P.Divergence of apoptosis-inducing and preventing signals in bacteria-faced macrophages through myeloid differentiation factor 88 and IL-1 receptor-associated kinase members.J Immunol. 2002;168(9):4601-4611.
141. Mayo MW, Wang CY, Cogswell PC , et al. Requirement of NF-κB activation to supress P53 - independent apoptosis induced by oncogenic Ras. Science . 1997 ; 278 :1812.
142. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. Opposingeffects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995;270:1326-1331.
143. New L, Jiang Y, Zhao M et al. PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J, 1998, 17 (12): 3372-3384.
144. 方希敏. 陈铭珍. 陈日玲.细胞色素 c 与凋亡的研究进展 国外医学.输血及血液学分册 2004;27(5):420-422.
145. Okamoto K ,Prives C. A role if cyclin G in the process of apoptosis. Oncogene,1999,18(32):4604-4615.
146. Morita N,Kiryu S,Kiyama H.p53-independent cyclin G expression in a group of mature neurons and its enhanced expression during nerve regeneration. J Nertosci.1996,16(19):5961-5966.
147. Mbebi C,See V, Mereken L, et al. Amyloid precursor protein family induced neuronal death is mediated by impairment of the neuropretecsive calcium/calmodulin protein kinase Ⅳ-dependent signaling pathway. J Biol Chem, 2002,277(23):20979-20990.
148. Loo DT , Copani AG, et al. Apoptosis is induced byβ2amyloid in culture central nervous system neurons. Proc Natl Acad Sci.1993;90 :7951-7955.
149. Wakasugi M, Kawashima A, Morioka H,et al. DDB accumulates at DNA damage sitesimmediately after uv irradiation and directly stimulates nucleotideexcision repair. J Biol Chem 2002;277:1637-1640.
150. Diehl JA, Yang W, Rimerman RA, et al .Hsc70 regulates accumulation of cyclin D1 and cyclin D1-dependent protein kinase.Mol Cell Biol. 2003;23(5):1764-1774.
151. Chen YC , Lin2Shiau SY, Lin JK, et al . Involvement of heat shock protein 70 and p53 proteins in attenuation of UVC induced apoptosis by thermal stress in hepatocellular carcinoma cells. Photochem Photobiol . 1999 ;70 :78-86.
152. Bose J, Gruber AD, Helming L, et al . The phosphatidylserine receptor has essential functions during embryogenesis but not in apoptotic cell removal.J Biol. 2004;3(4):15.
153. Lockhart AC, Tirona RG,Kim RB. Pharmacogenetics of ATP-binding cassette transporters in cancer and chemotherapy. Mol Cancer Ther, 2003,2(7): 685-698.
154. van der Kolk DM, Vellenga E , Muller M, et al . Multidrug resistance protein MRP1 , glutathione , and related enzymes , their importance in acute myloid leukemia . Adv Exp Med Biol ,1999 ;457 :187-198.
155. Wu L, Gu J, Weng Y, Kluetzman K, et al . Conditional knockout of the mouseNADPH-cytochrome p450 reductase gene.Genesis. 2003 ;36(4):177-81.
156. 于建洋,窦华林.头孢菌素类药物“双硫醒”样反应 52 例临床分析. 临床医学.2004;6:3.
157. Meech R , Mackenzie PI . Structure and function of uridine diphosphate glucuronosyltransferases . Clin Exp Pharmacol Physiol . 1 9 9 7 , 2 4 ( 1 2 ) : 9 0 7 - 9 1 5 .
158. 莫隽全,区庆嘉,何劲松. 小鼠 UGT1A1mRNA 在慢性肝损伤时的表达. 中国普通外科杂志.2003;12(4):276-279.
159. 卢洁玲.药物的不良反应.上海医药;1998;19(10):37-38.
160. Cao Jia, et al. Toxicogenomics and application and DNA microarrays. Chinese Journal of Pharmacology and Toxicology, 2000,14(5):336-340.
1. Vrana KE, Freeman WM, Aschner M. Use of microarray technologies in toxicology research [J]. Neurotoxicology. 2003, 24(3): 321-332.
2. Anderson NL,Matheson AD,Steiner S. Proteomics:applications in basic and applied biology [J]. Curr Opin Biotechnol. 2000 ,11(4 ): 408-412.
3. Huang J , Lih CJ, et al. Global analysis of growth phase responsive gene expression and regulation of antibiotic biosynthetic pathways in Streptomyces coelicolor using DNA microarrays [J]. Genes & development. 2001, 15 (23): 3183-3192.
4. Halgren RG, Fielden MR, Fong CJ, et al. Assessment of clone identity and sequence fidelity for 1189 IMAGE cDNA clones [J]. Nucleic Acids Res 2001, 29 (2): 582–588.
5. Lipshutz R, Fodor S ,Gingeras T, et al. High desity synthetic oligonucleotide arrays[J].Nature Gentics supplement. 1999,21(3): 20-24.
6. Shioda T. Application of DNA microarray to toxicological research [J]. J Environ Pathol Toxicol Oncol. 2004,23(1):13-31.
7. Robin L. Stears et al. Trends in microarray analysis [J]. Nat Med 2003, 1(9): 140-145.
8. Yang YH, Speed T . Design issues for cDNA microarray experiments [J] . Nat Rev Genet. 2002, 3(8):579-588.
9. Lee ML, Kuo FC, Whitmore GA, et al. Importance of replication in microarray gene expression studies: statistical methods and evidence from repetitive cDNA hybridizations.[J] Proc Natl Acad Sci U S A. 2000, 97(18):9834-9839.
10. Tilstone C. DNA microarrays: Vital statistics [J]. Nature 2003 , 424(6949): 610-612.
11. Bartosiewicz M, Trounstine M, Barker D et al. Development of a Toxicological Gene Array and Quantitative Assessment of This Technology [J]. Arch Biochem Biophys. 2000, 376(1):66-73.
12. Yue, H. et al. An evaluation of the performance of cDNA microarrays for detecting changes in global mRNA expression [J]. Nucleic Acids Res. 2001, 29(8):E41.
13. Brown C S, Goodwin P C, Sorgor P K . Image metrics in the statistical analysis of DNA microarray dat . [J]. Proc Natl Acad Sci U S A. 2001,98(16) :8944-8949.
14. Yang YH, Dudoit S, Luu P, et al. Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation [J]. Nucleic acids research. 2002, 30(4): E15.
15. Ideker T, Thorsson V, et al. Testing for differentially-expressed genes by maximum-likelihood analysis of microarray data [J]. J Comput Biol .2000, 7 (6) :805-817 .
16. Draghici S. Statistical intelligence: effective analysis of highdensity microarray data [J].Drug Discov Today 2002, 7 (11 Suppl): S55–S63.
17. Alon U, Barkai N, Notterman DA, et al. Broad patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays [J]. Proc Natl Acad Sci U S A. 1999, 96 (12): 6745–6750.
18. Zhou X , Kao MC, Wong WH . Transitive functional annotation by shortest-path anal-ysis of gen expression data [J]. Proc Natl Acad Sci U S A..2002,99 (20):12783-12788.
19. Brazma A, Hingamp P, Quackenbush J, et al Minimum information about a microarray experiment (MIAME)-toward standards for microarray data [J]. Nat Genet.2001 , 29(4):365-371.