细胞色素P450 3A4、谷胱甘肽硫转移酶A1基因转染人肝细胞系的建立及功能测定
|
摘要
严重肝脏疾病时的主要功能障碍之一,是药物在肝脏的代谢功能明显下降,从而导致药效降低,并会进一步加重肝脏损害,这主要与肝脏表达的药物代谢酶含量下降以及活性降低有关。为了解决这个问题,本研究将肝脏中较为重要的与药物代谢有关的Ⅰ相药物代谢酶—细胞色素P450 3A4(CYP 3A4)和Ⅱ相药物代谢酶—谷胱甘肽硫转移酶Al (GST A1)构建成一个双表达载体；同时,为了提高CYP3A4和GST A1的表达量,根据人类优势密码子将其基因进行优化后,构建成另一个双表达载体,分别将其转染肝脏肿瘤细胞系C3A中,以期能够增强C3A细胞的药物代谢的功能,在治疗严重肝脏疾病的病人中得到应用。
1.重组质粒的构建及鉴定本实验根据人类优势密码子对CYP 3A4和GST A1序列进行优化,由Invitrogen公司进行全基因合成,并将以上两个基因克隆到以pcDNA3.1 (+)载体为骨架的双CMV启动子载体中,构建质粒pcDNA3.1 (+)-OCYP 3A4-OGST A1,以该质粒为模板扩增优化过的OGSTA1和OCYP3A4基因。从含有GSTA1和CYP 3A4的克隆中扩增GSTA1和CYP3A4基因。将获得的4个片段经酶切、连接、转化等步骤最终构建成两个双表达的重组质粒：pBudCE4.1-CYP 3A4-GST A1和pBudCE4.1-OCYP 3A4-OGST A1,序列测定及分析结果表明所构建质粒符合应用要求。
2.转染肝细胞系的建立及功能评价将构建好的重组质粒pBudCE4.1-CYP 3A4-GST A1和pBudCE4.1-OCYP 3A4-OGST A1分别转染肝脏肿瘤细胞系C3A,用浓度为400μg／ml的Zeocin筛选出稳定转染的细胞系,成功构建了转染重组质粒pBudCE4.1-CYP 3A4-GST A1的细胞系,命名为C3A-未优势化；而转染重组质粒PBudCE4.1-OCYP 3A4-OGST A1的细胞虽有存活,但生长极为缓慢,至本论文完成之时仍未生长成单层细胞,目前正在进一步研究中。经MTT试验证明：CYP 3A4和／或GSTA1的表达量增加会导致细胞生长受到抑制。构建好的C3A-未优势化细胞系通过qPCR的方法检测其目的基因CYP 3A4和GST A1的表达量较正常C3A细胞系高；通过色谱法证明C3A-未优势化细胞系有明显的CYP 3A4活性,而正常C3A细胞系中CYP 3A4的表达活性较低,未检测到；用免疫组化实验证实C3A-未优势化细胞系中目的基因GST A1有表达,而正常C3A细胞系中的目的基因GST A1表达较低,未检测到；另外,C3A-未优势化细胞系对利多卡因的代谢能力亦有所增强,代谢率为62.5%,而正常C3A细胞系中的利多卡因代谢率仅为30%。结论：构建的C3A-未优势化细胞系功能有所改善,有望成为生物人工肝系统的细胞材料。
The hepatic metabolism of drug decreases obviously in patients with serious liver diseases.This reduced the drug effects and aggravated the liver damage, which is due to the declined expression and activity of drug metabolic enzyme. Therefore, we have targeted gene cytochrome P450 3A4 (CYP 3A4) and glutathione-S-transferase A1 (GST A1), which belonged to PhaseⅠand PhaseⅡdrug metabolic enzyme respectively. At the same time, we optimized the codons of CYP 3A4 and GST A1 to enhance the expression. The two vectors transfected C3A cell line and the function of drug metabolism was evaluated.
1. Construction and identification of recombinant plasmids The optimized CYP 3A4 and GST A1 were synthesized and cloned to pcDNA3.1(+) which had two CMV promoters. The recombinant plasmid was named pcDNA3.1(+)-OCYP 3A4-OGST A1. And we have gotten the OCYP 3A4 and OGST A1 gene by polymerase chain reaction(PCR) from this plasmid. By means of digestion, ligation and transformation, we got two recombinant plasmids, named pBudCE4.1-CYP 3A4-GST A1 and pBudCE4.1-OCYP 3A4-OGST A1 respectively, and confirmed by sequencing and blast analysis.
2. Establishment and function evaluation of transfected liver cell line C3A cell line were transfected with recombinant plasmids of pBudCE4.1-CYP 3A4-GST Al and pBudCE4.1-OCYP 3A4-OGST A1 respectively, and cultured with MEM containing 400μg/ml Zeocin for 2 weeks. The cell lines, named C3A-Unoptimized, expressed CYP 3A4 and GST A1 successfully and stably, while the cell lines expressed OCYP 3A4 and OGST Al unstably. By MTT assay, it showed that the cell growth would be inhibited by the increased expression of CYP 3A4 and GSTAl. The C3A-Unoptimized cell lines expressed more CYP 3A4 and GSTA1 than that of normal C3A cell line tested by qPCR. By chromatogram assay, it showed that the activity of CYP 3A4 existed in the C3A-Unoptimized cell lines whereas it was undetectable in normal C3A cell line. The immuno-histochemical staining indicated the higher expression of GSTA1 in C3A-Unoptimized cell lines than in normal C3A cell line. The ability of metabolizing lidocarine for the C3A-Unoptimized cell lines was enhanced (the metabolizing rate was 62.5%) comparing with that in normal C3A cell line (the metabolizing rate was 30%). Conclusions:The function of C3A-Unoptimized cell line have been improved, and this cell line might become a new cell material in the bioartificial liver support system.
1.重组质粒的构建及鉴定本实验根据人类优势密码子对CYP 3A4和GST A1序列进行优化,由Invitrogen公司进行全基因合成,并将以上两个基因克隆到以pcDNA3.1 (+)载体为骨架的双CMV启动子载体中,构建质粒pcDNA3.1 (+)-OCYP 3A4-OGST A1,以该质粒为模板扩增优化过的OGSTA1和OCYP3A4基因。从含有GSTA1和CYP 3A4的克隆中扩增GSTA1和CYP3A4基因。将获得的4个片段经酶切、连接、转化等步骤最终构建成两个双表达的重组质粒：pBudCE4.1-CYP 3A4-GST A1和pBudCE4.1-OCYP 3A4-OGST A1,序列测定及分析结果表明所构建质粒符合应用要求。
2.转染肝细胞系的建立及功能评价将构建好的重组质粒pBudCE4.1-CYP 3A4-GST A1和pBudCE4.1-OCYP 3A4-OGST A1分别转染肝脏肿瘤细胞系C3A,用浓度为400μg／ml的Zeocin筛选出稳定转染的细胞系,成功构建了转染重组质粒pBudCE4.1-CYP 3A4-GST A1的细胞系,命名为C3A-未优势化；而转染重组质粒PBudCE4.1-OCYP 3A4-OGST A1的细胞虽有存活,但生长极为缓慢,至本论文完成之时仍未生长成单层细胞,目前正在进一步研究中。经MTT试验证明：CYP 3A4和／或GSTA1的表达量增加会导致细胞生长受到抑制。构建好的C3A-未优势化细胞系通过qPCR的方法检测其目的基因CYP 3A4和GST A1的表达量较正常C3A细胞系高；通过色谱法证明C3A-未优势化细胞系有明显的CYP 3A4活性,而正常C3A细胞系中CYP 3A4的表达活性较低,未检测到；用免疫组化实验证实C3A-未优势化细胞系中目的基因GST A1有表达,而正常C3A细胞系中的目的基因GST A1表达较低,未检测到；另外,C3A-未优势化细胞系对利多卡因的代谢能力亦有所增强,代谢率为62.5%,而正常C3A细胞系中的利多卡因代谢率仅为30%。结论：构建的C3A-未优势化细胞系功能有所改善,有望成为生物人工肝系统的细胞材料。
The hepatic metabolism of drug decreases obviously in patients with serious liver diseases.This reduced the drug effects and aggravated the liver damage, which is due to the declined expression and activity of drug metabolic enzyme. Therefore, we have targeted gene cytochrome P450 3A4 (CYP 3A4) and glutathione-S-transferase A1 (GST A1), which belonged to PhaseⅠand PhaseⅡdrug metabolic enzyme respectively. At the same time, we optimized the codons of CYP 3A4 and GST A1 to enhance the expression. The two vectors transfected C3A cell line and the function of drug metabolism was evaluated.
1. Construction and identification of recombinant plasmids The optimized CYP 3A4 and GST A1 were synthesized and cloned to pcDNA3.1(+) which had two CMV promoters. The recombinant plasmid was named pcDNA3.1(+)-OCYP 3A4-OGST A1. And we have gotten the OCYP 3A4 and OGST A1 gene by polymerase chain reaction(PCR) from this plasmid. By means of digestion, ligation and transformation, we got two recombinant plasmids, named pBudCE4.1-CYP 3A4-GST A1 and pBudCE4.1-OCYP 3A4-OGST A1 respectively, and confirmed by sequencing and blast analysis.
2. Establishment and function evaluation of transfected liver cell line C3A cell line were transfected with recombinant plasmids of pBudCE4.1-CYP 3A4-GST Al and pBudCE4.1-OCYP 3A4-OGST A1 respectively, and cultured with MEM containing 400μg/ml Zeocin for 2 weeks. The cell lines, named C3A-Unoptimized, expressed CYP 3A4 and GST A1 successfully and stably, while the cell lines expressed OCYP 3A4 and OGST Al unstably. By MTT assay, it showed that the cell growth would be inhibited by the increased expression of CYP 3A4 and GSTAl. The C3A-Unoptimized cell lines expressed more CYP 3A4 and GSTA1 than that of normal C3A cell line tested by qPCR. By chromatogram assay, it showed that the activity of CYP 3A4 existed in the C3A-Unoptimized cell lines whereas it was undetectable in normal C3A cell line. The immuno-histochemical staining indicated the higher expression of GSTA1 in C3A-Unoptimized cell lines than in normal C3A cell line. The ability of metabolizing lidocarine for the C3A-Unoptimized cell lines was enhanced (the metabolizing rate was 62.5%) comparing with that in normal C3A cell line (the metabolizing rate was 30%). Conclusions:The function of C3A-Unoptimized cell line have been improved, and this cell line might become a new cell material in the bioartificial liver support system.
引文
1. Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likeli-hood of metabolic pharmacokinetic interactions.Clin Pharmacokinet, 1997,32:210-258.
2. Hoyumpa AM, Schenker S. Is glucuronidation truly preserved in patients with liver disease? Hepatology,1991,13(4):786-795.
3. Farrell G. Effects of disease on expression and regulation of CYPs. Mol Aspects Med.1999,20(1-2):55-70.
4. Nelson DR, Koymans L, Kamataki T,et al. P450 superfamily:update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics,1996,6:1-42.
5. McKinnon RA, Burgess WM, Hall PM,et al. Characterisation of CYP3 A gene subfamily expression in human gastrointestinal tissues. Gut,1995,36(2): 259-267.
6. Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases. World J Gastroenterol,2003,9(2):359-363.
7. Lown K, Kolars J, Turgeon K, et al. The erythromycin breath test selectively measures P450ⅢA in patients with severe liver disease. Clin Pharmacol Ther. 1992,51(3):229-238.
8. Huet PM, Villeneuve JP. Determinants of drug disposition in patients with cirrhosis. Hepatology,1983,3(6):913-918.
9. Kleinbloesem CH, van Harten J, Wilson JP, et al. Nifedipine:kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration. Clin Pharmacol Ther.1986,40(1):21-28.
10. Chalasani N, Gorski JC, Patel NH, et al. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis:effects of transjugular intrahepatic portosystemic shunts. Hepatology,2001,34(6):1103-1108.
11. Blackburn AC, Tzeng HF, Anders MW, et al. Discovery of a functional polymorphism in human glutathione transferase zeta by expressed sequence tag database analysis. Pharmacogenetics,2000,10(1):49-57.
12. Strange RC, Spiteri MA, Ramachandran S, et al.Glutathione-S-transferase family of enzymes. Mutat Res,2001,482(1-2):21-26.
13. Johansson AS, Mannervik B. Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones. J Biol Chem,2001,276(35):33061-33065.
14. Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene,2003,22(47):7369-7375.
15. Hamdan FF, Mousa Ai, Ribeiro P. Codon optimization improves heterologous expression of a Schistosoma mansoni cDNA in HEK293 cells. Parasitol Res,2002,88(6):583-586.
16. Disbrow GL, Sunitha I, Baker CC, et al. Codon optimization of the HPV-16 E5 gene enhances protein expression. Virology,2003,311 (1):105-114.
17. Kim CH, Oh Y, Lee TH. Codon optimization for high level expression of human erythropoietin(EPO) in mammalian cells. Gene,1997,199 (1-2): 293-301.
18. Deml L, Bojak A, Steck S, et al. Multiple effects of codon usage optimization on expression and immunogenicity of DNA candidate vaccines encoding the human immunodeficiency virus type 1 Gag protein. J Virol,2001,75 (22): 10991-11001.
19.张相民,王世峰,辛伟,等.密码子偏性对痘苗病毒载体表达效率影响的研究.病毒学报,2006,22(5)：350-357.
20.张相民,辛伟,王世峰,‘等-按痘苗病毒优势密码子改造HIV21 gag基因提高表达水平的研究.病毒学报,2005,21(3)：210-216.
21.石秀凡,黄京飞,柳树群,等.人类基因同义密码子偏好的特征以及与基因GC含量的关系.生物化学与生物物理进展,2002,29(3)：411-414.
1. Chamuleau RA, Deurholt T, Hoekstra R. Which are the right cells to be used in a bioartificial liver? Metabolic Brain Disease.2005,20(4):327-335.
2. Hoque ME, Mao HQ, Ramakrishna S, et al. Hybrid braided 3-D scaffold for bioartificial liver assist device. J Biomater Sci Polymer Edn.2007,18(1): 45-58.
3.刘鸿凌,辛绍杰,貌盼勇.生物人工肝支持系统中细胞材料的选择.中国组织工程研究与临床康复.2007,11(47)：9561-9564.
4. McKinnon RA, Burgess WM, Hall PM, et al. Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues. Gut,1995,36(2):259-267.
5. Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases. World J Gastroenterol,2003,9(2):359-363.
6. Lown K, Kolars J, Turgeon K, et al. The erythromycin breath test selectively measures P450ⅢA in patients with severe liver disease. Clin Pharmacol Ther, 1992,51(3):229-238.
7. Chalasani N, GorskiJC, Patel NH, et al. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis:effects of transjugular intrahepatic portosystemic shunts. Hepatology,2001,34(6):1103-1108.
8. Hayes JD, McLellan Ll. Glatathione and glutathione-dependent enzymes respresent a co-ordinately regulated defence against oxidative stress.Free Rad Res,1999,31(4):273-300.
9. Strange RC, Spiteri MA, Ramachandran S, et al. Glutathione-S-transferase family of enzymes. Mutat Res,2001,482(1-2):21-26.
10. Johansson AS, Mannervik B. Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones. J Biol Chem,2001,276(35):33061-33065.
11.乔惠萍,徐加英,焦旸,等.GSTθ高表达抑制宫颈癌HeLa细胞的生长和增加放射敏感性.中国医药指南,2008,6(23)：239-243.
12.乔惠萍,焦肠,徐加英,等.GSTθ转染对HCT116细胞系的影响.苏州大学学报(医学版),2009,29(1)：7-10.
13. Gillespie JR, Uversky VN. Structure and function of alpha-fetoprotein:a biophysical overview. Biochimica et Biophysica Acta,2000,1480(1-2):41-56.
14. Oertel M, Menthena A, Chen YQ, et al. Properties of cryopreserved fetal liver stem/progenitor cells that exhibit long-term repopulation of the normal rat liver. Stem Cells,2006,24(10):2244-2251.
15. Schnater JM, Bruder E, Bertschin S, et al. Subcutaneous and intrahepatic growth of human hepatoblastoma in immunodeficient mice. J Hepatol,2006, 45(3):377-386.
16. Mizejewski GJ. Biological roles of alpha-fetoprotein during pregnancy and perinatal development. Exp Biol Med(Maywood),2004,229(6):439-463.
17. Dudich E, Semenkova L, Dudich I, et al. Alpha-fetoprotein antagonizes X-linked inhibitor of apoptosis protein anticaspase activity and disrupts XIAP-caspase interaction. FEBS J,2006,273(16):3837-3849.
18. Ritter M, Ali MY, Grimm CF, et al. Immunoregulation of dendritic and T cells by alpha-fetoprotein in patients with hepatocellular carcinoma. J Hepatol, 2004,41(6):999-1007.
19. Li MS, Ma QL, Chen Q, et al. Alpha-fetoprotein triggers hepatoma cells escaping from immune surveillance through altering the expression of Fas/FasL and tumor necrosis factor related apoptosis-inducing ligand and its receptor of lymphocytes and liver cancer cells. World J Gastroenterol,2005, 11(17):2564-2569.
20. Leerapun A, Suravarapu SV, Bida JP, et al.The utility of lens culinaris agglutinin-reactive alpha-fetoprotein in the diagnosis of hepatocellular carcinoma:evaluation in a United States referral population. Clin Gastroenterol Hepatol,2007,5(3):394-402.
21.Montaser LM, Abbas OM, Saltah AM, et al. Circulating AFP mRNA as a possible indicator of hematogenous spread of HCC cells:a possilbe association with HBV infection. J Egypt Natl Canc Inst,2007,19(1):48-60.
22.石明,张颖,钟崇,等.肝癌患者围手术期外周血甲胎蛋白mRNA表达与术后复发的关系.癌症,2008,27(1)：83-87.
23. Mizejewski GJ. Levels of alpha-fetoprotein during pregnancy and early infancy in normal and disease states. Obstet Gynecol Surv,2003,58(12):804-826.
24. Dashe JS, Twickler DM, Santos-Ramos R, et al. Alpha-fetoprotein detection of neural tube defects and the impact of standard ultrasound. Am J Obstet Gymecol,2006,195(6):1623-1628.
25. Rozenberg P, Bussieres L, Chevret S, et al. Screening for Down syndrome using first-trimester combined screening followed by second-trimester ultrasound examination in an unselected population. Am J Obstet Gynecol, 2006,195(6):1379-1387.
26. Odibo SO, Sehdev HM, Stamilio DM, et al. Evaluting the thresholds of abnormal secong trimester multiple marker screening tests associated with intra-uterine growth restriction. Am J Perinatol,2006,23(6):363-367.
27. Wald NJ, Morris JK, Ibison J, et al.Screening in early pregnancy for preeclampsia using Down syndrome quadruple test markers. Prenat Diagn, 2006,26(6):559-564.
28. Rausch DN, Lambert-Messerlian GM, Canick JA. Participation in maternal serum for Down Syndrome, neural tube defects and trisomy 18 following screen-posotive results in a previouw pregnancy. West J Med,2000,173(3): 180-183.
29. Kiran TS, Bethel J, Bhal PS. Correlation of abnormal second trimester maternal serum alpha-fetoprotein (MSAFP) levels and adverse pregnancy outcome. J Obstet Gynaecol,2005,25(3):253-256.
30. Butterfield LH. Recent advances in immunotherapy for hepatocellular cancer. Swiss Med Wkly,2007,137(5-6):83-90.
1. Kemper B. Structural basis for the role in protein folding of conserved proline-rich regions in cytochromes P450. Toxicol Appl Pharmacol,2004, 199(3):305-315.
2. Nelson DR, Zeldin DC, Hoffman SM, et al. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes, and alternative-splice variants. Pharmacogenetics,2004,14(1):1-18.
3. Phillips KA, Veenstra DL, Oren E, et al. Potential role of pharmacogenomics in reducing adverse drug reactions:a systematic review. J Am Med Assoc, 2001,286:2270-2279.
4. Williams JA, Hyland R, Jones BC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates:A pharmacokinetic explanation for typically observed low exposure AUCi/AUC ratios. Drug Metab Dispos,2004, 32(11):1201-1208.
5. Kalgutkar AS, Gardner I, Obach RS, et al. A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab,2005, 6(3):161-225.
6. Laine JE, Auriola S, Pasanen M, et al. Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes. Xenobiotica,2009, 39(1):11-21.
7. Chen C, Krausz KW, Idle JR,et al.Identification of novel toxicity-associated metabolites by metabolomics and mass isotopomer analysis of acetaminophen metabolism in wild-type and Cyp2el-null mice. J Biol Chem,2008, 283(8):4543-4559.
8. Davies BJ, Herbert MK, Coller JK, et al. Determination of the 4-monohydroxy metabolites of perhexiline in human plasma, urine and liver microsomes by liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci,2006,843(2):302-309.
9. Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease.Clin Liver Dis,2002,6(3):755-774.
10. Obermayer-Straub P, Strassburg CP, Manns MP. Target proteins in human autoimmunity:cytochromes P450 and UDP-glucuronosyltransferases. Can J Gastroenterol,2000,14(5):429-439.
11. Cederbaum AI, Lu Y, Wu D. Role of oxidative stress in alcohol-induced liver injury. Arch Toxicol,2009,83(6):519-548.
12. Lu Y, Cederbaum AI. CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med,2008,44(5):723-738.
13.Natori S, Rust C, Stadheim LM, et al. Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis. J Hepatol,2001,34(2):248-253.
14. Vidali M, Stewart SF, Rolla R, et al. Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease. Hepatology,2003,37(2):410-419.
15. Jiang J, Torok N. Nonalcoholic steatohepatitis and the metabolic syndrome. Metab Syndr Relat Disord,2008,6(1):1-7.
16. Nagata K, Suzuki H, Sakaguchi S. Common pathogenic mechanism in development progression of liver injury caused by non-alcoholic or alcoholic steatohepatitis. J Toxicol Sci,2007,32(5):453-468.
17. Emery MG, Fisher JM, Chien JY, et al. CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease. Hepatology,2003,38(2):428-435.
18. Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis:association of insulin resistance and mitochondrial abnormalities. Gastroenterology,2001 120(5):1183-1192.
19. Wei Y, Rector RS, Thyfault JP, et al. Nonalcoholic fatty liver disease and mitochondrial dysfunction.World J Gastroenterol,2008,14(2):193-199.
20. Leclercq IA, Farrell GC, Field J, et al. CYP2E1 and CYP4A as as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest,2000,105(8):1067-1075.
21. Robertson G, Leclercq I, Farrell GC. Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress. Am J Physiol Gastrointest Liver Physiol,2001,281(5):G1135-1139.
22. Hirose Y, Naito Z, Kato S, et al. Immunohistochemical study of CYP2E1 in hepatocellular carcinoma carcinogenesis:examination with newly prepared anti-human CYP2E1 antibody. J Nippon Med Sch,2002,69(3):243-251.
23.盛鹰,黄天壬,张振权,等.广西壮族人群肝癌家族聚集与细胞色素P4502E1基因多态性等因素关系的研究.中华流行病学杂志,2009,03(2)：151-155.
24. McLean M, Dutton MF. Cellular interactions and metabolism of aflatoxin:an update. Pharmacol Ther,1995,65(2):163-192.
25. Burckart GJ, Frye RF, Kelly P, et al. Induction of CYP2E1 activity in liver transplant patients as measured by chlorzoxazone 6-hydroxylation. Clin Pharmacol Ther,1998,63(3):296-302.
26. Park JM, Lin YS, Calamia JC, et al. Transiently altered acetaminophen metabolism after liver transplantation. Clin Pharmacol Ther,2003,73(6):545-553.
27. Farrell G. Effects of disease on expression and regulation of CYPs. Mol Aspects Med,1999,20(1-2):55-70.
28. George J, Murray M, Byth K, et al. Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology,1995,21(1):120-128.
29. Coverdale SA, Samarasinghe DA, Lin R, et al. Changes in antipyrine clearance and platelet count, but not conventional liver tests, correlate with fibrotic change in chronic hepatitis C:value for predicting fibrotic progression. Am J Gastroenterol,2003,98(6):1384-1390.
30. Kh Hakooz NM. Caffeine metabolic ratios for the in vivo evaluation of CYP1A2,N-acetyltransferase 2, xanthine oxidase and CYP2A6 enzymatic activities. Curr Drug Metab,2009,10(4):329-338.
31. Pique JM, Feu F, de Prada G, et al. Pharmacokinetics of omeprazole given by continuous intravenous infusion to patients with varying degrees of hepatic dysfunction. Clin Pharmaco kinet,2002,41(12):999-1004.
32. Kirchheiner J, Roots I, Goldammer M, et al. Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs:clinical relevance. Clin Pharmacokinet,2005,44(12):1209-1225.
33. Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases. World J Gastroenterol,2003,9(2):359-363.
34. Chalasani N, Gorski JC, Patel NH, et al. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis:effects of transjugular intrahepatic portosystemic shunts. Hepatology,2001,34(6):1103-1108.
35. Wolbold R, Klein K, Burk O, et al. Sex is a major determinant of CYP3A4 expression in human liver. Hepatology,2003,38(4):978-988.
1. Blackburn AC, Tzeng HF, Anders MW, et al. Discovery of a functional polymorphism in human glutathione transferase zeta by expressed sequence tag database analysis. Pharmacogenetics,2000,10(1):49-57.
2. Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol,2005,45:51-88.
3. Jakobsson P-J, Morgenstern R, Mancini J, et al.Common structural features of MAPEG-a widespread superfamily of membrane associated proteins with highly divergent functions in eicosanoid and glutathione metabolism. Protein Sci,1999,8(3):689-692.
4. Jakobsson P-J,Thoren S, Morgenstern R,et al. Identification of human prostaglandin E synthase:A microsomal,glutathione-dependent,inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci USA, 1999,96(13):7220-7225.
5. Strange RC, Spiteri MA, Ramachandran S, et al.Glutathione-S-transferase family of enzymes. Mutat Res,2001,482(1-2):21-26.
6. Adler V, Yin Z, Fuchs SY, et al. Regulation of JNK signaling by GSTPp. EMBO JK,1999,18(5):321-1334.
7. Yin Z, Ivanov VN, Habelhah H, et al. Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases. Cancer Res,2000,60(15):4053-4057.
8. Johansson AS, Mannervik B. Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones. J Biol Chem,2001,276(35):33061-33065.
9. Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene,2003,22(47):7369-7375.
10. Coles B, Nowell SA, MacLeod SL, et al. The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk. Mutat Res,2001,482(1-2):3-10.
11. Tetlow N, Coggan M, Casarotto MG, et al. Functional polymorphism of human glutathione transferase A3:effects on xenobiotic metabolism and steroid biosynthesis. Pharmacogenetics,2004,14(10):657-663.
12. Chuang ST, Chu P, Sugimura J, et al. Overexpression of glutathione s-transferase alpha in clear cell renal cell carcinoma. Am J Clin Pathol,2005, 123(3):421-429.
13. Ning B, Wang C, Morel F, et al. Human glutathione S-transferase A2 polymorphisms:variant expression, distribution in prostate cancer cases/controls and a novel form. Pharmacogenetics,2004,14(1):35-44.
14. Johansson AS, Mannervik B. Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones. J Biol Chem,2001,276(35):33061-33065.
15. Tetlow N, Coggan M, Casarotto MG,et al. Functional polymorphism of human glutathione transferase A3:effects on xenobiotic metabolism and steroid biosynthesis. Pharmacogenetics,2004,14(10):657-663.
16. Tiltman AJ, Ali H. Distribution of alpha glutathione S-transferase in ovarian neoplasms:an immunohistochemical study. Histopathology,2001,39(3): 266-272.
17. Townsend D, Tew K. Cancer drugs, genetic variation and the glutathione-S-transferase gene family. Am J Pharmacogenomics,2003,3(3):157-172.
18. Board PG, Coggan M, Chelvanayagam G, et al. Identification, characterization, and crystal structure . of the Omega class glutathione transferases. J Biol Chem,2000,275(32):24798-24806.
19. Yin ZL, Dahlstrom JE, Le Couteur DG, et al. Immunohistochemistry of omega class glutathione S-transferase in human tissues. J Histochem Cytochem,2001,49(8):983-987.
20. Whitbread AK, Tetlow N, Eyre-HJ, et al.Characterization of the human Omega class glutathione transferase genes and associated polymorphisms. Pharmacogenetics,2003,13(3):131-144.
21. Wang L, Xu J, Ji C, et al. Cloning, expression and characterization of human glutathione S-transferase Omega 2. Int J Mol Med,2005,16(1):19-27.
22. Fernandez-Canon JM, Baetscher MW, Finegold M, et al. Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism. Mol Cell Biol,2002,22(13): 4943-4951.
23. Blackburn AC, Coggan M, Tzeng HF, et al. GSTZ1d:a new allele of glutathione transferase zeta and maleylacetoacetate isomerase. Pharmacogenetics,2001,11(8):671-678.
24. Guo X, Dixit V, Liu H, et al. Inhibition and recovery of rat hepatic glutathione S-transferase zeta and alteration of tyrosine metabolism following dichloroacetate exposure and withdrawal. Drug Metab Dispos,2006,34(1): 36-42.
25. Smith G, Stanley LA, Sim E, et al. Metabolic polymorphisms and cancer susceptibility. Cancer Surv,1995,25:27-65.
26. Lohmueller KE, Pearce CL, Pike M, et al. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet,2003,33(2):177-182.
27. Ambrosone CB, Sweeney C, Coles BF, et al. Polymorphisms in glutathione S-transferases (GSTM1 and GSTT1) and survival after treatment for breast cancer. Cancer Res,2001,61(19):7130-7135.
28. Howells RE, Holland T, Dhar KK, et al. Glutathione S-transferase GSTM1 and GSTT1 genotypes in ovarian cancer:association with p53 expression and survival. Int J Gynecol Cancer,2001,11(2):107-112.
29. Beuckmann CT, Fujimori K, Urade Y, et al. Identification of mu-class glutathione transferases M2-2 and M3-3 as cytosolic prostaglandin E synthases in the human brain. Neurochem Res,2000,25(5):733-738.
30. Baez S, Segura-Aguilar J, Widersten M, et al. Glutathione transferases catalyse the detoxication of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes. Biochem J,1997,324(Part 1):25-28.
31. Hand PA, Inskip A, Gilford J, et al. Allelism at the glutathione S-transferase GSTM3 locus:interactions with GSTM1 and GSTT1 as risk factors for astrocytoma. Carcinogenesis,1996,17(9):1919-1922.
32. Matthias C, Bockmuhl U, Jahnke V, et al. Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers:studies in upper aerodigestive tract cancers. Pharmacogenetics,1998,8(2):91-100.
33. Yengi L, Inskip A, Gilford J,et al. Polymorphism at the glutathione S-transferase locus GSTM3:interactions with cytochrome P450 and glutathione S-transferase genotypes as risk factors for multiple cutaneous basal cell carcinoma. Cancer Res,1996,56(9):1974-1977.
34. Strange RC, Fryer AA. The glutathione S-transferases:influence of polymorphism on cancer susceptibility. IARC Sci Publ,1999,148:231-249.
35. Mondal BC, Paria N, Majumdar S, et al. Glutathione S-transferase M1 and T1 null genotype frequency in chronic myeloid leukaemia. Eur J Cancer Prev 2005,14(3):281-284.
36. Garte S, Gaspari L, Alexandrie AK,et al. Metabolic gene polymorphism frequencies in control populations.Cancer Epidemiol Biomark Prev,2001,10 (12):1239-1248.
37. Alexandrie AK, Rannug A, Juronen E,et al. Detection and characterization of a novel functional polymorphism in the GSTT1 gene. Pharmacogenetics, 2002,12(8):613-619.
38. Tew KD. Glutathione-associated enzymes in anticancer drug resistance. Cancer Res,1994,54(16):4313-4320.
39. Dang DT, Chen F, Kohli M,et al. Glutathione S-transferase pi1 promotes tumorigenicity in HCT116 human colon cancer cells. Cancer Res,2005, 65(20):9485-9494.
40. Nelson WG, De Marzo AM, Deweese TL, et al. Preneoplastic prostate lesions: an opportunity for prostate cancer prevention. Ann NY Acad Sci,2001,952: 135-144.
41. Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene,2003,22 (47):7369-7375.
42. Wang T, Arifoglu P, Ronai Z, et al. Glutathione S-transferase P1-1 (GSTP1-1) inhibits c-Jun N-terminal kinase (JNK1) signaling through interaction with the C terminus. J Biol Chem,2001,276(24):20999-21003.
43. van Zanden JJ, Ben Hamman O, van Iersel ML, et al. Inhibition of human glutathione S-transferase P1-1 by the flavonoid quercetin. Chem Biol Interact, 2003,145(2):139-148.
44. Mukanganyama S, Widersten M, Naik YS, et al. Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer,2002,97(5):700-705.
45. van Haaften RI, Haenen GR, van Bladeren PJ, et al. Inhibition of various glutathione S-transferase isoenzymes by RRR-alpha-tocopherol.Toxicol In Vitro,2003,17(3):245-251.
46. Ricci G, De Maria F,Antonini G, et al.7-Nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases. Mechanism of action of potential anticancer drugs. J Biol Chem,2005, 280(28):26397-26405.
47. Turella P, Cerella C, Filomeni G, et al. Proapoptotic activity of new glutathione S-transferase inhibitors.Cancer Res,2005,65(9):3751-3761.
48. Rosen LS, Laxa B, Boulos L, et al. Phase 1 study of TLK286 (Telcyta) administered weekly in advanced malignancies. Clin Cancer Res,2004, 10(11):3689-3698.
49. Gunnarsdottir S, Elfarra AA. Cytotoxicity of the novel glutathione-activated thiopurine prodrugs cis-AVTP [cis-6-(2-acetylvinylthio)purine] and trans-AVTG [trans-6-(2-acetylvinylthio)guanine] results from the National Cancer Institute's anticancer drug screen. Drug Metab Dispos,2004, 32(3):321-327.
50. Ibarra C, Grillo MP, Lo Bello M, et al. Exploration of in vitro pro-drug activation and futile cycling by glutathione S-transferases:thiol ester hydrolysis and inhibitor maturation. Arch Biochem Biophys,2003,414(2): 303-311.
51. Zhao Z, Koeplinger KA, Peterson T, et al. Mechanism, structure-activity studies, and potential applications of glutathione S-transferase-catalyzed cleavage of sulfonamides. Drug Metab Dispos,1999,27(9):992-998.
52. Findlay VJ, Townsend DM, Saavedra JE, et al. Tumor cell responses to a novel glutathione S-transferase-activated nitric oxide-releasing prodrug. Mol Pharmacol,2004,65(5):1070-1079.
53. Pezzola S, Antonini G, Geroni C,et al. Role of glutathione transferases in the mechanism of brostallicin activation. Biochemistry,2010,49(1):226-35.
2. Hoyumpa AM, Schenker S. Is glucuronidation truly preserved in patients with liver disease? Hepatology,1991,13(4):786-795.
3. Farrell G. Effects of disease on expression and regulation of CYPs. Mol Aspects Med.1999,20(1-2):55-70.
4. Nelson DR, Koymans L, Kamataki T,et al. P450 superfamily:update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics,1996,6:1-42.
5. McKinnon RA, Burgess WM, Hall PM,et al. Characterisation of CYP3 A gene subfamily expression in human gastrointestinal tissues. Gut,1995,36(2): 259-267.
6. Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases. World J Gastroenterol,2003,9(2):359-363.
7. Lown K, Kolars J, Turgeon K, et al. The erythromycin breath test selectively measures P450ⅢA in patients with severe liver disease. Clin Pharmacol Ther. 1992,51(3):229-238.
8. Huet PM, Villeneuve JP. Determinants of drug disposition in patients with cirrhosis. Hepatology,1983,3(6):913-918.
9. Kleinbloesem CH, van Harten J, Wilson JP, et al. Nifedipine:kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration. Clin Pharmacol Ther.1986,40(1):21-28.
10. Chalasani N, Gorski JC, Patel NH, et al. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis:effects of transjugular intrahepatic portosystemic shunts. Hepatology,2001,34(6):1103-1108.
11. Blackburn AC, Tzeng HF, Anders MW, et al. Discovery of a functional polymorphism in human glutathione transferase zeta by expressed sequence tag database analysis. Pharmacogenetics,2000,10(1):49-57.
12. Strange RC, Spiteri MA, Ramachandran S, et al.Glutathione-S-transferase family of enzymes. Mutat Res,2001,482(1-2):21-26.
13. Johansson AS, Mannervik B. Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones. J Biol Chem,2001,276(35):33061-33065.
14. Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene,2003,22(47):7369-7375.
15. Hamdan FF, Mousa Ai, Ribeiro P. Codon optimization improves heterologous expression of a Schistosoma mansoni cDNA in HEK293 cells. Parasitol Res,2002,88(6):583-586.
16. Disbrow GL, Sunitha I, Baker CC, et al. Codon optimization of the HPV-16 E5 gene enhances protein expression. Virology,2003,311 (1):105-114.
17. Kim CH, Oh Y, Lee TH. Codon optimization for high level expression of human erythropoietin(EPO) in mammalian cells. Gene,1997,199 (1-2): 293-301.
18. Deml L, Bojak A, Steck S, et al. Multiple effects of codon usage optimization on expression and immunogenicity of DNA candidate vaccines encoding the human immunodeficiency virus type 1 Gag protein. J Virol,2001,75 (22): 10991-11001.
19.张相民,王世峰,辛伟,等.密码子偏性对痘苗病毒载体表达效率影响的研究.病毒学报,2006,22(5)：350-357.
20.张相民,辛伟,王世峰,‘等-按痘苗病毒优势密码子改造HIV21 gag基因提高表达水平的研究.病毒学报,2005,21(3)：210-216.
21.石秀凡,黄京飞,柳树群,等.人类基因同义密码子偏好的特征以及与基因GC含量的关系.生物化学与生物物理进展,2002,29(3)：411-414.
1. Chamuleau RA, Deurholt T, Hoekstra R. Which are the right cells to be used in a bioartificial liver? Metabolic Brain Disease.2005,20(4):327-335.
2. Hoque ME, Mao HQ, Ramakrishna S, et al. Hybrid braided 3-D scaffold for bioartificial liver assist device. J Biomater Sci Polymer Edn.2007,18(1): 45-58.
3.刘鸿凌,辛绍杰,貌盼勇.生物人工肝支持系统中细胞材料的选择.中国组织工程研究与临床康复.2007,11(47)：9561-9564.
4. McKinnon RA, Burgess WM, Hall PM, et al. Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues. Gut,1995,36(2):259-267.
5. Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases. World J Gastroenterol,2003,9(2):359-363.
6. Lown K, Kolars J, Turgeon K, et al. The erythromycin breath test selectively measures P450ⅢA in patients with severe liver disease. Clin Pharmacol Ther, 1992,51(3):229-238.
7. Chalasani N, GorskiJC, Patel NH, et al. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis:effects of transjugular intrahepatic portosystemic shunts. Hepatology,2001,34(6):1103-1108.
8. Hayes JD, McLellan Ll. Glatathione and glutathione-dependent enzymes respresent a co-ordinately regulated defence against oxidative stress.Free Rad Res,1999,31(4):273-300.
9. Strange RC, Spiteri MA, Ramachandran S, et al. Glutathione-S-transferase family of enzymes. Mutat Res,2001,482(1-2):21-26.
10. Johansson AS, Mannervik B. Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones. J Biol Chem,2001,276(35):33061-33065.
11.乔惠萍,徐加英,焦旸,等.GSTθ高表达抑制宫颈癌HeLa细胞的生长和增加放射敏感性.中国医药指南,2008,6(23)：239-243.
12.乔惠萍,焦肠,徐加英,等.GSTθ转染对HCT116细胞系的影响.苏州大学学报(医学版),2009,29(1)：7-10.
13. Gillespie JR, Uversky VN. Structure and function of alpha-fetoprotein:a biophysical overview. Biochimica et Biophysica Acta,2000,1480(1-2):41-56.
14. Oertel M, Menthena A, Chen YQ, et al. Properties of cryopreserved fetal liver stem/progenitor cells that exhibit long-term repopulation of the normal rat liver. Stem Cells,2006,24(10):2244-2251.
15. Schnater JM, Bruder E, Bertschin S, et al. Subcutaneous and intrahepatic growth of human hepatoblastoma in immunodeficient mice. J Hepatol,2006, 45(3):377-386.
16. Mizejewski GJ. Biological roles of alpha-fetoprotein during pregnancy and perinatal development. Exp Biol Med(Maywood),2004,229(6):439-463.
17. Dudich E, Semenkova L, Dudich I, et al. Alpha-fetoprotein antagonizes X-linked inhibitor of apoptosis protein anticaspase activity and disrupts XIAP-caspase interaction. FEBS J,2006,273(16):3837-3849.
18. Ritter M, Ali MY, Grimm CF, et al. Immunoregulation of dendritic and T cells by alpha-fetoprotein in patients with hepatocellular carcinoma. J Hepatol, 2004,41(6):999-1007.
19. Li MS, Ma QL, Chen Q, et al. Alpha-fetoprotein triggers hepatoma cells escaping from immune surveillance through altering the expression of Fas/FasL and tumor necrosis factor related apoptosis-inducing ligand and its receptor of lymphocytes and liver cancer cells. World J Gastroenterol,2005, 11(17):2564-2569.
20. Leerapun A, Suravarapu SV, Bida JP, et al.The utility of lens culinaris agglutinin-reactive alpha-fetoprotein in the diagnosis of hepatocellular carcinoma:evaluation in a United States referral population. Clin Gastroenterol Hepatol,2007,5(3):394-402.
21.Montaser LM, Abbas OM, Saltah AM, et al. Circulating AFP mRNA as a possible indicator of hematogenous spread of HCC cells:a possilbe association with HBV infection. J Egypt Natl Canc Inst,2007,19(1):48-60.
22.石明,张颖,钟崇,等.肝癌患者围手术期外周血甲胎蛋白mRNA表达与术后复发的关系.癌症,2008,27(1)：83-87.
23. Mizejewski GJ. Levels of alpha-fetoprotein during pregnancy and early infancy in normal and disease states. Obstet Gynecol Surv,2003,58(12):804-826.
24. Dashe JS, Twickler DM, Santos-Ramos R, et al. Alpha-fetoprotein detection of neural tube defects and the impact of standard ultrasound. Am J Obstet Gymecol,2006,195(6):1623-1628.
25. Rozenberg P, Bussieres L, Chevret S, et al. Screening for Down syndrome using first-trimester combined screening followed by second-trimester ultrasound examination in an unselected population. Am J Obstet Gynecol, 2006,195(6):1379-1387.
26. Odibo SO, Sehdev HM, Stamilio DM, et al. Evaluting the thresholds of abnormal secong trimester multiple marker screening tests associated with intra-uterine growth restriction. Am J Perinatol,2006,23(6):363-367.
27. Wald NJ, Morris JK, Ibison J, et al.Screening in early pregnancy for preeclampsia using Down syndrome quadruple test markers. Prenat Diagn, 2006,26(6):559-564.
28. Rausch DN, Lambert-Messerlian GM, Canick JA. Participation in maternal serum for Down Syndrome, neural tube defects and trisomy 18 following screen-posotive results in a previouw pregnancy. West J Med,2000,173(3): 180-183.
29. Kiran TS, Bethel J, Bhal PS. Correlation of abnormal second trimester maternal serum alpha-fetoprotein (MSAFP) levels and adverse pregnancy outcome. J Obstet Gynaecol,2005,25(3):253-256.
30. Butterfield LH. Recent advances in immunotherapy for hepatocellular cancer. Swiss Med Wkly,2007,137(5-6):83-90.
1. Kemper B. Structural basis for the role in protein folding of conserved proline-rich regions in cytochromes P450. Toxicol Appl Pharmacol,2004, 199(3):305-315.
2. Nelson DR, Zeldin DC, Hoffman SM, et al. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes, and alternative-splice variants. Pharmacogenetics,2004,14(1):1-18.
3. Phillips KA, Veenstra DL, Oren E, et al. Potential role of pharmacogenomics in reducing adverse drug reactions:a systematic review. J Am Med Assoc, 2001,286:2270-2279.
4. Williams JA, Hyland R, Jones BC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates:A pharmacokinetic explanation for typically observed low exposure AUCi/AUC ratios. Drug Metab Dispos,2004, 32(11):1201-1208.
5. Kalgutkar AS, Gardner I, Obach RS, et al. A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab,2005, 6(3):161-225.
6. Laine JE, Auriola S, Pasanen M, et al. Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes. Xenobiotica,2009, 39(1):11-21.
7. Chen C, Krausz KW, Idle JR,et al.Identification of novel toxicity-associated metabolites by metabolomics and mass isotopomer analysis of acetaminophen metabolism in wild-type and Cyp2el-null mice. J Biol Chem,2008, 283(8):4543-4559.
8. Davies BJ, Herbert MK, Coller JK, et al. Determination of the 4-monohydroxy metabolites of perhexiline in human plasma, urine and liver microsomes by liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci,2006,843(2):302-309.
9. Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease.Clin Liver Dis,2002,6(3):755-774.
10. Obermayer-Straub P, Strassburg CP, Manns MP. Target proteins in human autoimmunity:cytochromes P450 and UDP-glucuronosyltransferases. Can J Gastroenterol,2000,14(5):429-439.
11. Cederbaum AI, Lu Y, Wu D. Role of oxidative stress in alcohol-induced liver injury. Arch Toxicol,2009,83(6):519-548.
12. Lu Y, Cederbaum AI. CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med,2008,44(5):723-738.
13.Natori S, Rust C, Stadheim LM, et al. Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis. J Hepatol,2001,34(2):248-253.
14. Vidali M, Stewart SF, Rolla R, et al. Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease. Hepatology,2003,37(2):410-419.
15. Jiang J, Torok N. Nonalcoholic steatohepatitis and the metabolic syndrome. Metab Syndr Relat Disord,2008,6(1):1-7.
16. Nagata K, Suzuki H, Sakaguchi S. Common pathogenic mechanism in development progression of liver injury caused by non-alcoholic or alcoholic steatohepatitis. J Toxicol Sci,2007,32(5):453-468.
17. Emery MG, Fisher JM, Chien JY, et al. CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease. Hepatology,2003,38(2):428-435.
18. Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis:association of insulin resistance and mitochondrial abnormalities. Gastroenterology,2001 120(5):1183-1192.
19. Wei Y, Rector RS, Thyfault JP, et al. Nonalcoholic fatty liver disease and mitochondrial dysfunction.World J Gastroenterol,2008,14(2):193-199.
20. Leclercq IA, Farrell GC, Field J, et al. CYP2E1 and CYP4A as as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest,2000,105(8):1067-1075.
21. Robertson G, Leclercq I, Farrell GC. Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress. Am J Physiol Gastrointest Liver Physiol,2001,281(5):G1135-1139.
22. Hirose Y, Naito Z, Kato S, et al. Immunohistochemical study of CYP2E1 in hepatocellular carcinoma carcinogenesis:examination with newly prepared anti-human CYP2E1 antibody. J Nippon Med Sch,2002,69(3):243-251.
23.盛鹰,黄天壬,张振权,等.广西壮族人群肝癌家族聚集与细胞色素P4502E1基因多态性等因素关系的研究.中华流行病学杂志,2009,03(2)：151-155.
24. McLean M, Dutton MF. Cellular interactions and metabolism of aflatoxin:an update. Pharmacol Ther,1995,65(2):163-192.
25. Burckart GJ, Frye RF, Kelly P, et al. Induction of CYP2E1 activity in liver transplant patients as measured by chlorzoxazone 6-hydroxylation. Clin Pharmacol Ther,1998,63(3):296-302.
26. Park JM, Lin YS, Calamia JC, et al. Transiently altered acetaminophen metabolism after liver transplantation. Clin Pharmacol Ther,2003,73(6):545-553.
27. Farrell G. Effects of disease on expression and regulation of CYPs. Mol Aspects Med,1999,20(1-2):55-70.
28. George J, Murray M, Byth K, et al. Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology,1995,21(1):120-128.
29. Coverdale SA, Samarasinghe DA, Lin R, et al. Changes in antipyrine clearance and platelet count, but not conventional liver tests, correlate with fibrotic change in chronic hepatitis C:value for predicting fibrotic progression. Am J Gastroenterol,2003,98(6):1384-1390.
30. Kh Hakooz NM. Caffeine metabolic ratios for the in vivo evaluation of CYP1A2,N-acetyltransferase 2, xanthine oxidase and CYP2A6 enzymatic activities. Curr Drug Metab,2009,10(4):329-338.
31. Pique JM, Feu F, de Prada G, et al. Pharmacokinetics of omeprazole given by continuous intravenous infusion to patients with varying degrees of hepatic dysfunction. Clin Pharmaco kinet,2002,41(12):999-1004.
32. Kirchheiner J, Roots I, Goldammer M, et al. Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs:clinical relevance. Clin Pharmacokinet,2005,44(12):1209-1225.
33. Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases. World J Gastroenterol,2003,9(2):359-363.
34. Chalasani N, Gorski JC, Patel NH, et al. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis:effects of transjugular intrahepatic portosystemic shunts. Hepatology,2001,34(6):1103-1108.
35. Wolbold R, Klein K, Burk O, et al. Sex is a major determinant of CYP3A4 expression in human liver. Hepatology,2003,38(4):978-988.
1. Blackburn AC, Tzeng HF, Anders MW, et al. Discovery of a functional polymorphism in human glutathione transferase zeta by expressed sequence tag database analysis. Pharmacogenetics,2000,10(1):49-57.
2. Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol,2005,45:51-88.
3. Jakobsson P-J, Morgenstern R, Mancini J, et al.Common structural features of MAPEG-a widespread superfamily of membrane associated proteins with highly divergent functions in eicosanoid and glutathione metabolism. Protein Sci,1999,8(3):689-692.
4. Jakobsson P-J,Thoren S, Morgenstern R,et al. Identification of human prostaglandin E synthase:A microsomal,glutathione-dependent,inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci USA, 1999,96(13):7220-7225.
5. Strange RC, Spiteri MA, Ramachandran S, et al.Glutathione-S-transferase family of enzymes. Mutat Res,2001,482(1-2):21-26.
6. Adler V, Yin Z, Fuchs SY, et al. Regulation of JNK signaling by GSTPp. EMBO JK,1999,18(5):321-1334.
7. Yin Z, Ivanov VN, Habelhah H, et al. Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases. Cancer Res,2000,60(15):4053-4057.
8. Johansson AS, Mannervik B. Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones. J Biol Chem,2001,276(35):33061-33065.
9. Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene,2003,22(47):7369-7375.
10. Coles B, Nowell SA, MacLeod SL, et al. The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk. Mutat Res,2001,482(1-2):3-10.
11. Tetlow N, Coggan M, Casarotto MG, et al. Functional polymorphism of human glutathione transferase A3:effects on xenobiotic metabolism and steroid biosynthesis. Pharmacogenetics,2004,14(10):657-663.
12. Chuang ST, Chu P, Sugimura J, et al. Overexpression of glutathione s-transferase alpha in clear cell renal cell carcinoma. Am J Clin Pathol,2005, 123(3):421-429.
13. Ning B, Wang C, Morel F, et al. Human glutathione S-transferase A2 polymorphisms:variant expression, distribution in prostate cancer cases/controls and a novel form. Pharmacogenetics,2004,14(1):35-44.
14. Johansson AS, Mannervik B. Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones. J Biol Chem,2001,276(35):33061-33065.
15. Tetlow N, Coggan M, Casarotto MG,et al. Functional polymorphism of human glutathione transferase A3:effects on xenobiotic metabolism and steroid biosynthesis. Pharmacogenetics,2004,14(10):657-663.
16. Tiltman AJ, Ali H. Distribution of alpha glutathione S-transferase in ovarian neoplasms:an immunohistochemical study. Histopathology,2001,39(3): 266-272.
17. Townsend D, Tew K. Cancer drugs, genetic variation and the glutathione-S-transferase gene family. Am J Pharmacogenomics,2003,3(3):157-172.
18. Board PG, Coggan M, Chelvanayagam G, et al. Identification, characterization, and crystal structure . of the Omega class glutathione transferases. J Biol Chem,2000,275(32):24798-24806.
19. Yin ZL, Dahlstrom JE, Le Couteur DG, et al. Immunohistochemistry of omega class glutathione S-transferase in human tissues. J Histochem Cytochem,2001,49(8):983-987.
20. Whitbread AK, Tetlow N, Eyre-HJ, et al.Characterization of the human Omega class glutathione transferase genes and associated polymorphisms. Pharmacogenetics,2003,13(3):131-144.
21. Wang L, Xu J, Ji C, et al. Cloning, expression and characterization of human glutathione S-transferase Omega 2. Int J Mol Med,2005,16(1):19-27.
22. Fernandez-Canon JM, Baetscher MW, Finegold M, et al. Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism. Mol Cell Biol,2002,22(13): 4943-4951.
23. Blackburn AC, Coggan M, Tzeng HF, et al. GSTZ1d:a new allele of glutathione transferase zeta and maleylacetoacetate isomerase. Pharmacogenetics,2001,11(8):671-678.
24. Guo X, Dixit V, Liu H, et al. Inhibition and recovery of rat hepatic glutathione S-transferase zeta and alteration of tyrosine metabolism following dichloroacetate exposure and withdrawal. Drug Metab Dispos,2006,34(1): 36-42.
25. Smith G, Stanley LA, Sim E, et al. Metabolic polymorphisms and cancer susceptibility. Cancer Surv,1995,25:27-65.
26. Lohmueller KE, Pearce CL, Pike M, et al. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet,2003,33(2):177-182.
27. Ambrosone CB, Sweeney C, Coles BF, et al. Polymorphisms in glutathione S-transferases (GSTM1 and GSTT1) and survival after treatment for breast cancer. Cancer Res,2001,61(19):7130-7135.
28. Howells RE, Holland T, Dhar KK, et al. Glutathione S-transferase GSTM1 and GSTT1 genotypes in ovarian cancer:association with p53 expression and survival. Int J Gynecol Cancer,2001,11(2):107-112.
29. Beuckmann CT, Fujimori K, Urade Y, et al. Identification of mu-class glutathione transferases M2-2 and M3-3 as cytosolic prostaglandin E synthases in the human brain. Neurochem Res,2000,25(5):733-738.
30. Baez S, Segura-Aguilar J, Widersten M, et al. Glutathione transferases catalyse the detoxication of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes. Biochem J,1997,324(Part 1):25-28.
31. Hand PA, Inskip A, Gilford J, et al. Allelism at the glutathione S-transferase GSTM3 locus:interactions with GSTM1 and GSTT1 as risk factors for astrocytoma. Carcinogenesis,1996,17(9):1919-1922.
32. Matthias C, Bockmuhl U, Jahnke V, et al. Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers:studies in upper aerodigestive tract cancers. Pharmacogenetics,1998,8(2):91-100.
33. Yengi L, Inskip A, Gilford J,et al. Polymorphism at the glutathione S-transferase locus GSTM3:interactions with cytochrome P450 and glutathione S-transferase genotypes as risk factors for multiple cutaneous basal cell carcinoma. Cancer Res,1996,56(9):1974-1977.
34. Strange RC, Fryer AA. The glutathione S-transferases:influence of polymorphism on cancer susceptibility. IARC Sci Publ,1999,148:231-249.
35. Mondal BC, Paria N, Majumdar S, et al. Glutathione S-transferase M1 and T1 null genotype frequency in chronic myeloid leukaemia. Eur J Cancer Prev 2005,14(3):281-284.
36. Garte S, Gaspari L, Alexandrie AK,et al. Metabolic gene polymorphism frequencies in control populations.Cancer Epidemiol Biomark Prev,2001,10 (12):1239-1248.
37. Alexandrie AK, Rannug A, Juronen E,et al. Detection and characterization of a novel functional polymorphism in the GSTT1 gene. Pharmacogenetics, 2002,12(8):613-619.
38. Tew KD. Glutathione-associated enzymes in anticancer drug resistance. Cancer Res,1994,54(16):4313-4320.
39. Dang DT, Chen F, Kohli M,et al. Glutathione S-transferase pi1 promotes tumorigenicity in HCT116 human colon cancer cells. Cancer Res,2005, 65(20):9485-9494.
40. Nelson WG, De Marzo AM, Deweese TL, et al. Preneoplastic prostate lesions: an opportunity for prostate cancer prevention. Ann NY Acad Sci,2001,952: 135-144.
41. Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene,2003,22 (47):7369-7375.
42. Wang T, Arifoglu P, Ronai Z, et al. Glutathione S-transferase P1-1 (GSTP1-1) inhibits c-Jun N-terminal kinase (JNK1) signaling through interaction with the C terminus. J Biol Chem,2001,276(24):20999-21003.
43. van Zanden JJ, Ben Hamman O, van Iersel ML, et al. Inhibition of human glutathione S-transferase P1-1 by the flavonoid quercetin. Chem Biol Interact, 2003,145(2):139-148.
44. Mukanganyama S, Widersten M, Naik YS, et al. Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer,2002,97(5):700-705.
45. van Haaften RI, Haenen GR, van Bladeren PJ, et al. Inhibition of various glutathione S-transferase isoenzymes by RRR-alpha-tocopherol.Toxicol In Vitro,2003,17(3):245-251.
46. Ricci G, De Maria F,Antonini G, et al.7-Nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases. Mechanism of action of potential anticancer drugs. J Biol Chem,2005, 280(28):26397-26405.
47. Turella P, Cerella C, Filomeni G, et al. Proapoptotic activity of new glutathione S-transferase inhibitors.Cancer Res,2005,65(9):3751-3761.
48. Rosen LS, Laxa B, Boulos L, et al. Phase 1 study of TLK286 (Telcyta) administered weekly in advanced malignancies. Clin Cancer Res,2004, 10(11):3689-3698.
49. Gunnarsdottir S, Elfarra AA. Cytotoxicity of the novel glutathione-activated thiopurine prodrugs cis-AVTP [cis-6-(2-acetylvinylthio)purine] and trans-AVTG [trans-6-(2-acetylvinylthio)guanine] results from the National Cancer Institute's anticancer drug screen. Drug Metab Dispos,2004, 32(3):321-327.
50. Ibarra C, Grillo MP, Lo Bello M, et al. Exploration of in vitro pro-drug activation and futile cycling by glutathione S-transferases:thiol ester hydrolysis and inhibitor maturation. Arch Biochem Biophys,2003,414(2): 303-311.
51. Zhao Z, Koeplinger KA, Peterson T, et al. Mechanism, structure-activity studies, and potential applications of glutathione S-transferase-catalyzed cleavage of sulfonamides. Drug Metab Dispos,1999,27(9):992-998.
52. Findlay VJ, Townsend DM, Saavedra JE, et al. Tumor cell responses to a novel glutathione S-transferase-activated nitric oxide-releasing prodrug. Mol Pharmacol,2004,65(5):1070-1079.
53. Pezzola S, Antonini G, Geroni C,et al. Role of glutathione transferases in the mechanism of brostallicin activation. Biochemistry,2010,49(1):226-35.