臺灣博碩士論文加值系統

麩胱甘肽轉移酶(Glutathione S-transferase, GST)是細胞毒物代謝機轉中的主要解毒酵素之ㄧ，它牽涉代謝細胞內的有毒物質，並減少毒性物質對細胞的傷害。過去本實驗室證實，穩定表現GST M2於H1355肺癌細胞株可有效的降低經由BPDE所造成的DNA adducts。本研究以RT-PCR與Real-time PCR分析正常肺細胞株(MRC-5、WI-38與Beas-2B)與肺癌細胞株(H1355、H1299、A549、Calu-1、CH27、H23、CL 1-0與CL 1-5)中GST M2 mRNA的表現。結果顯示，肺癌細胞株的GST M2基因表現量比正常肺細胞株低。但無論在正常肺細胞株或肺癌細胞株中，皆可發現另一GST isoform : GST Pi的表現，唯只有H1355肺癌細胞株偵測不到GST Pi的表現量。以Real-time PCR分析肺癌組織其GST M2基因表現量，結果發現比旁邊非腫瘤部分大約降低了7倍; GST Pi在肺癌組織的表現量比旁邊非腫瘤部分高大約2倍。當肺癌組織GST M2表現量喪失時，患者之預後有較差的趨勢。此外，GST M2基因並非因genomic DNA缺失而造成在肺癌細胞株中GST M2基因表現降低。將H1355細胞分別或共同處理(1)histone deacetylase(HDAC)inhibitor : TSA 及 demethylation agent : 5-aza-2’-deoxycytidine(5-aza-dC)，皆無法回復GST M2基因的表現。因此，推測H1355細胞株中GST M2的不表現，並非因為啟動子的CpG發生甲基化或組織蛋白去乙醯化所造成。經Luciferase reporter 分析其promoter上多形性(C128T)位置，也與 GST M2 基因表現降低無關。因此H1355肺癌細胞株中GST M2表現量降低的機轉，仍待進一步釐清以彗星分析法的結果指出，GST M2可降低B[a]P對DNA的傷害。並且GST M2降低H1355細胞株經B[a]P處理後所造成細胞週期之S與G2/M phase堆積。綜言之，肺癌的成因與預後不佳可能與GST M2的喪失有關。

Glutathione S transferases(GSTs)are a family of phase II detoxification enzymes that catalyse the conjuation of glutatione(GSH)to a wide variety of endogenous and exogenous electrophilic compounds. In our previous studies, we found that the overexpression of GST M2 gene in H1355 cells prevented BPDE-mediated formation of DNA adducts. Furthermore, by using RT PCR and Real time-PCR, we found that the expression level of GST M2 was lower in lung cancer cells in comparison to normal lung cells. GST Pi expressed both in lung cancer cells and normal lung cells. However, in H1355 cells, GST Pi can not be detected by RT PCR. In comparison with adjacent normal tissue, expression level of GST M2, analyzed by Real Time-PCR, in lung tumor tissue was seven-times lower. However, expression of GST Pi in adjacent normal tissue was two-times higher than that in lung tumor tissue. Poor prognosis is associated with the low expression of GST M2 in lung tumor tissue. Undetectable expression of GST M2 in H1355 was not caused by the deletion of genomic DNA. The reduced expression GST M2 in H1355 cells can not be restored after treatments with histone deacetylase inhibitor: TSA or/and demethylation agent: 5-aza-dC. Neither the methylation of CpG in promoter nor the histone deacetylation contributed to the reduced expression of GST M2 in H1355 cells. The promoter activity of GST M2 was not associated with the polymorphism(C128T)in its promoter by using luciferase reporter assay. Further investigations will be needed to clarify the mechanisms of GST M2 down regulation in lung cancer cells. Comet assay demonstrated that overexpression of GST M2 in H1355 could alleviate B[a]P-mediated DNA damage. Additionally, overexpression of GST M2 in H1355 cells would alleviate B[a]P-mediated S and G2/M phase accumulation. Therefore, these results of this study suggest that lung carcinogenesis and poor prognosis of overall survival were associated with the reduced expression of GST M2 gene.

頁次
目錄 1
壹、 中文摘要 2
貳、 英文摘要 4
參、 縮寫表 6
肆、 緒論 8
伍、 研究動機 18
陸、 實驗設計 20
柒、 實驗材料 25
捌、 實驗方法 30
玖、 結果 57
拾、 討論 70
拾壹、 圖表說明 81
拾貳、 附圖與附表 106
拾參、 參考文獻 109

Adler, V., Yin, Z., Fuchs, S.Y., Benezra, M., Rosario, L., Tew, K.D., Pincus, M.R., Sardana, M., Henderson, C.J., Wolf, C.R., Davis, R.J. and Ronai, Z.(1999)Regulation of JNK signaling by GSTp. EMBO J, 18, 1321-1334.
Alberg, A.J., Brock, M.V. and Samet, J.M.(2005)Epidemiology of lung cancer: looking to the future. J Clin Oncol, 23, 3175-3185.
Anttila, S., Hirvonen, A., Vainio, H., Husgafvel-Pursiainen, K., Hayes, J.D. and Ketterer, B.(1993)Immunohistochemical localization of glutathione S-transferases in human lung. Cancer Res, 53, 5643-5648.
Asakura, T., Sasagawa, A., Takeuchi, H., Shibata, S., Marushima, H., Mamori, S. and Ohkawa, K.(2007)Conformational change in the active center region of GST P1-1, due to binding of a synthetic conjugate of DXR with GSH, enhanced JNK-mediated apoptosis. Apoptosis, 12, 1269-1280.
Baez, S., Segura-Aguilar, J., Widersten, M., Johansson, A.S. and Mannervik, B.(1997)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, 324( Pt 1), 25-28.
Bain, C., Feskanich, D., Speizer, F.E., Thun, M., Hertzmark, E., Rosner, B.A. and Colditz, G.A.(2004)Lung cancer rates in men and women with comparable histories of smoking. J Natl Cancer Inst, 96, 826-834.
Banoglu, E.(2000)Current status of the cytosolic sulfotransferases in the metabolic activation of promutagens and procarcinogens. Curr Drug Metab, 1, 1-30.
Booth, J., Boyland, E. and Sims, P.(1961)An enzyme from rat liver catalysing conjugations with glutathione. Biochem J, 79, 516-524.
Carrillo, M.C., Favre, C., Carnovale, C.E., Monti, J.A., Alvarez, M.L., Scapini, C., Pisani, G.B. and Lugano, M.C.(2001)Involvement of mu class glutathione S-transferase subunit M2(rGST M2)levels in the initiation and promotion of hepatocellular carcinogenesis in old rats. Exp Gerontol, 36, 255-265.
Castro, V.M., Soderstrom, M., Carlberg, I., Widersten, M., Platz, A. and Mannervik, B.(1990)Differences among human tumor cell lines in the expression of glutathione transferases and other glutathione-linked enzymes. Carcinogenesis, 11, 1569-1576.
Cavalieri, E.L. and Rogan, E.G.(1995)Central role of radical cations in metabolic activation of polycyclic aromatic hydrocarbons. Xenobiotica, 25, 677-688.
Chang, J.T., Chang, H., Chen, P.H., Lin, S.L. and Lin, P.(2007)Requirement of aryl hydrocarbon receptor overexpression for CYP1B1 up-regulation and cell growth in human lung adenocarcinomas. Clin Cancer Res, 13, 38-45.
Cho, S.G., Lee, Y.H., Park, H.S., Ryoo, K., Kang, K.W., Park, J., Eom, S.J., Kim, M.J., Chang, T.S., Choi, S.Y., Shim, J., Kim, Y., Dong, M.S., Lee, M.J., Kim, S.G., Ichijo, H. and Choi, E.J.(2001)Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1. J Biol Chem, 276, 12749-12755.
Curran, J.E., Weinstein, S.R. and Griffiths, L.R.(2000)Polymorphisms of glutathione S-transferase genes(GSTM1, GSTP1 and GSTT1)and breast cancer susceptibility. Cancer Lett, 153, 113-120.
Das, P.M. and Singal, R.(2004)DNA methylation and cancer. J Clin Oncol, 22, 4632-4642.
Denissenko, M.F., Pao, A., Tang, M. and Pfeifer, G.P.(1996)Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science, 274, 430-432.
Dipple, A.(1995)DNA adducts of chemical carcinogens. Carcinogenesis, 16, 437-441.
Dolado, I., Swat, A., Ajenjo, N., De Vita, G., Cuadrado, A. and Nebreda, A.R.(2007)p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis. Cancer Cell, 11, 191-205.
Dorion, S., Lambert, H. and Landry, J.(2002)Activation of the p38 signaling pathway by heat shock involves the dissociation of glutathione S-transferase Mu from Ask1. J Biol Chem, 277, 30792-30797.
Duaso, M.J., De Irala, J. and Canga, N.(2006)Employee''s perceived exposure to environmental tobacco smoke, passive smoking risk beliefs and attitudes towards smoking: a case study in a university setting. Health Educ Res, 21, 26-33.
Eaton, D.L. and Bammler, T.K.(1999)Concise review of the glutathione S-transferases and their significance to toxicology. Toxicol Sci, 49, 156-164.
Eklund, B.I., Gunnarsdottir, S., Elfarra, A.A. and Mannervik, B.(2007)Human glutathione transferases catalyzing the bioactivation of anticancer thiopurine prodrugs. Biochem Pharmacol, 73, 1829-1841.
Eklund, B.I. and Mannervik, B.(2007)Importance of a hypervariable active-site residue in human Mu class glutathione transferases catalyzing the bioactivation of chemotherapeutic thiopurine prodrugs. Biochim Biophys Acta.
Esteller, M., Corn, P.G., Baylin, S.B. and Herman, J.G.(2001)A gene hypermethylation profile of human cancer. Cancer Res, 61, 3225-3229.
Feng, Z., Hu, W., Hu, Y. and Tang, M.S.(2006)Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair. Proc Natl Acad Sci U S A, 103, 15404-15409.
Fields, W.R., Morrow, C.S., Doss, A.J., Sundberg, K., Jernstrom, B. and Townsend, A.J.(1998)Overexpression of stably transfected human glutathione S-transferase P1-1 protects against DNA damage by benzo[a]pyrene diol-epoxide in human T47D cells. Mol Pharmacol, 54, 298-304.
Garry, S., Nesslany, F., Aliouat, E., Haguenoer, J.M. and Marzin, D.(2003)Assessment of genotoxic effect of benzo[a]pyrene in endotracheally treated rat using the comet assay. Mutat Res, 534, 33-43.
Guengerich, F.P.(2003)Cytochromes P450, drugs, and diseases. Mol Interv, 3, 194-204.
Guengerich, F.P., McCormick, W.A. and Wheeler, J.B.(2003)Analysis of the kinetic mechanism of haloalkane conjugation by mammalian theta-class glutathione transferases. Chem Res Toxicol, 16, 1493-1499.
Guo, N., Faller, D.V. and Vaziri, C.(2002)Carcinogen-induced S-phase arrest is Chk1 mediated and caffeine sensitive. Cell Growth Differ, 13, 77-86.
Hamilton, D.S., Zhang, X., Ding, Z., Hubatsch, I., Mannervik, B., Houk, K.N., Ganem, B. and Creighton, D.J.(2003)Mechanism of the glutathione transferase-catalyzed conversion of antitumor 2-crotonyloxymethyl-2-cycloalkenones to GSH adducts. J Am Chem Soc, 125, 15049-15058.
Harris, C.C.(1991)Chemical and physical carcinogenesis: advances and perspectives for the 1990s. Cancer Res, 51, 5023s-5044s.
Hayes, J.D., Flanagan, J.U. and Jowsey, I.R.(2005)Glutathione transferases. Annu Rev Pharmacol Toxicol, 45, 51-88.
Hayes, J.D. and Pulford, D.J.(1995)The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol, 30, 445-600.
Hecht, S.S.(1999)Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst, 91, 1194-1210.
Hecht, S.S.(2003)Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer, 3, 733-744.
Hoffmann, D., Hoffmann, I. and El-Bayoumy, K.(2001)The less harmful cigarette: a controversial issue. a tribute to Ernst L. Wynder. Chem Res Toxicol, 14, 767-790.
Iijima, H., Tomizawa, Y., Iwasaki, Y., Sato, K., Sunaga, N., Dobashi, K., Saito, R., Nakajima, T., Minna, J.D. and Mori, M.(2006)Genetic and epigenetic inactivation of LTF gene at 3p21.3 in lung cancers. Int J Cancer, 118, 797-801.
Innocenti, F., Grimsley, C., Das, S., Ramirez, J., Cheng, C., Kuttab-Boulos, H., Ratain, M.J. and Di Rienzo, A.(2002)Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics, 12, 725-733.
Iqbal, O.(2002)Pharmacogenomics in anticoagulant drug development. Pharmacogenomics, 3, 823-828.
Ishikawa, T.(1992)The ATP-dependent glutathione S-conjugate export pump. Trends Biochem Sci, 17, 463-468.
Jiang, H., Vudathala, D.K., Blair, I.A. and Penning, T.M.(2006)Competing roles of aldo-keto reductase 1A1 and cytochrome P4501B1 in benzo[a]pyrene-7,8-diol activation in human bronchoalveolar H358 cells: role of AKRs in P4501B1 induction. Chem Res Toxicol, 19, 68-78.
Keppler, D.(1999)Export pumps for glutathione S-conjugates. Free Radic Biol Med, 27, 985-991.
Klaassen, C.D.(2002)Xenobiotic transporters: another protective mechanism for chemicals. Int J Toxicol, 21, 7-12.
Ko, Y.C.(1996)[Air pollution and its health effects on residents in Taiwanese communities]. Kaohsiung J Med Sci, 12, 657-669.
Kushman, M.E., Kabler, S.L., Fleming, M.H., Ravoori, S., Gupta, R.C., Doehmer, J., Morrow, C.S. and Townsend, A.J.(2007)Expression of human glutathione S-transferase P1 confers resistance to benzo[a]pyrene or benzo[a]pyrene-7,8-dihydrodiol mutagenesis, macromolecular alkylation and formation of stable N2-Gua-BPDE adducts in stably transfected V79MZ cells co-expressing hCYP1A1. Carcinogenesis, 28, 207-214.
Lee, R.F. and Steinert, S.(2003)Use of the single cell gel electrophoresis/comet assay for detecting DNA damage in aquatic(marine and freshwater)animals. Mutat Res, 544, 43-64.
Li, D., Wang, M., Cheng, L., Spitz, M.R., Hittelman, W.N. and Wei, Q.(1996)In vitro induction of benzo(a)pyrene diol epoxide-DNA adducts in peripheral lymphocytes as a susceptibility marker for human lung cancer. Cancer Res, 56, 3638-3641.
Lin, P., Chang, J.T., Ko, J.L., Liao, S.H. and Lo, W.S.(2004)Reduction of androgen receptor expression by benzo[alpha]pyrene and 7,8-dihydro-9,10-epoxy-7,8,9,10-tetrahydrobenzo[alpha]pyrene in human lung cells. Biochem Pharmacol, 67, 1523-1530.
Liu, P., Barkley, L.R., Day, T., Bi, X., Slater, D.M., Alexandrow, M.G., Nasheuer, H.P. and Vaziri, C.(2006)The Chk1-mediated S-phase checkpoint targets initiation factor Cdc45 via a Cdc25A/Cdk2-independent mechanism. J Biol Chem, 281, 30631-30644.
Matsukawa, J., Matsuzawa, A., Takeda, K. and Ichijo, H.(2004)The ASK1-MAP kinase cascades in mammalian stress response. J Biochem(Tokyo), 136, 261-265.
McIlwain, C.C., Townsend, D.M. and Tew, K.D.(2006)Glutathione S-transferase polymorphisms: cancer incidence and therapy. Oncogene, 25, 1639-1648.
Mitra, S., Boldogh, I., Izumi, T. and Hazra, T.K.(2001)Complexities of the DNA base excision repair pathway for repair of oxidative DNA damage. Environ Mol Mutagen, 38, 180-190.
Mountain, C.F.(1997)Revisions in the International System for Staging Lung Cancer. Chest, 111, 1710-1717.
Nesnow, S., Ross, J.A., Mass, M.J. and Stoner, G.D.(1998)Mechanistic relationships between DNA adducts, oncogene mutations, and lung tumorigenesis in strain A mice. Exp Lung Res, 24, 395-405.
Olive, P.L. and Banath, J.P.(2006)The comet assay: a method to measure DNA damage in individual cells. Nat Protoc, 1, 23-29.
Penning, T.M., Burczynski, M.E., Hung, C.F., McCoull, K.D., Palackal, N.T. and Tsuruda, L.S.(1999)Dihydrodiol dehydrogenases and polycyclic aromatic hydrocarbon activation: generation of reactive and redox active o-quinones. Chem Res Toxicol, 12, 1-18.
Piipari, R., Nurminen, T., Savela, K., Hirvonen, A., Mantyla, T. and Anttila, S.(2003)Glutathione S-transferases and aromatic DNA adducts in smokers'' bronchoalveolar macrophages. Lung Cancer, 39, 265-272.
Revel, A., Raanani, H., Younglai, E., Xu, J., Han, R., Savouret, J.F. and Casper, R.F.(2001)Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects sperm from DNA damage and apoptosis caused by benzo(a)pyrene. Reprod Toxicol, 15, 479-486.
Ricci, G., De Maria, F., Antonini, G., Turella, P., Bullo, A., Stella, L., Filomeni, G., Federici, G. and Caccuri, A.M.(2005)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, 280, 26397-26405.
Richiardi, L., Boffetta, P., Simonato, L., Forastiere, F., Zambon, P., Fortes, C., Gaborieau, V. and Merletti, F.(2004)Occupational risk factors for lung cancer in men and women: a population-based case-control study in Italy. Cancer Causes Control, 15, 285-294.
Sagredo, C., Ovrebo, S., Haugen, A., Fujii-Kuriyama, Y., Baera, R., Botnen, I.V. and Mollerup, S.(2006)Quantitative analysis of benzo[a]pyrene biotransformation and adduct formation in Ahr knockout mice. Toxicol Lett, 167, 173-182.
Shao, G., Berenguer, J., Borczuk, A.C., Powell, C.A., Hei, T.K. and Zhao, Y.(2006)Epigenetic inactivation of Betaig-h3 gene in human cancer cells. Cancer Res, 66, 4566-4573.
Sheehan, D., Meade, G., Foley, V.M. and Dowd, C.A.(2001)Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem J, 360, 1-16.
Smith, C.J., Perfetti, T.A., Rumple, M.A., Rodgman, A. and Doolittle, D.J.(2000)"IARC group 2A Carcinogens" reported in cigarette mainstream smoke. Food Chem Toxicol, 38, 371-383.
Srivastava, S.K., Hu, X., Xia, H., Bleicher, R.J., Zaren, H.A., Orchard, J.L., Awasthi, S. and Singh, S.V.(1998)ATP-dependent transport of glutathione conjugate of 7beta, 8alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene in murine hepatic canalicular plasma membrane vesicles. Biochem J, 332( Pt 3), 799-805.
Steinkellner, H., Hoelzl, C., Uhl, M., Cavin, C., Haidinger, G., Gsur, A., Schmid, R., Kundi, M., Bichler, J. and Knasmuller, S.(2005)Coffee consumption induces GSTP in plasma and protects lymphocytes against(+/-)-anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide induced DNA-damage: results of controlled human intervention trials. Mutat Res, 591, 264-275.
Sundberg, K., Dreij, K., Seidel, A. and Jernstrom, B.(2002)Glutathione conjugation and DNA adduct formation of dibenzo[a,l]pyrene and benzo[a]pyrene diol epoxides in V79 cells stably expressing different human glutathione transferases. Chem Res Toxicol, 15, 170-179.
Tew, K.D.(2005)TLK-286: a novel glutathione S-transferase-activated prodrug. Expert Opin Investig Drugs, 14, 1047-1054.
Tew, K.D., Monks, A., Barone, L., Rosser, D., Akerman, G., Montali, J.A., Wheatley, J.B. and Schmidt, D.E., Jr.(1996)Glutathione-associated enzymes in the human cell lines of the National Cancer Institute Drug Screening Program. Mol Pharmacol, 50, 149-159.
Townsend, D.M. and Tew, K.D.(2003)The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene, 22, 7369-7375.
Toyokuni, S.(2006)Novel aspects of oxidative stress-associated carcinogenesis. Antioxid Redox Signal, 8, 1373-1377.
Turella, P., Cerella, C., Filomeni, G., Bullo, A., De Maria, F., Ghibelli, L., Ciriolo, M.R., Cianfriglia, M., Mattei, M., Federici, G., Ricci, G. and Caccuri, A.M.(2005)Proapoptotic activity of new glutathione S-transferase inhibitors. Cancer Res, 65, 3751-3761.
Veglia, F., Matullo, G. and Vineis, P.(2003)Bulky DNA adducts and risk of cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev, 12, 157-160.
Viegi, G., Simoni, M., Scognamiglio, A., Baldacci, S., Pistelli, F., Carrozzi, L. and Annesi-Maesano, I.(2004)Indoor air pollution and airway disease. Int J Tuberc Lung Dis, 8, 1401-1415.
Virmani, A.K., Tsou, J.A., Siegmund, K.D., Shen, L.Y., Long, T.I., Laird, P.W., Gazdar, A.F. and Laird-Offringa, I.A.(2002)Hierarchical clustering of lung cancer cell lines using DNA methylation markers. Cancer Epidemiol Biomarkers Prev, 11, 291-297.
Wang, H. and LeCluyse, E.L.(2003)Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet, 42, 1331-1357.
Wang, X., Pavelic, Z.P., Li, Y., Gleich, L., Gartside, P.S., Pavelic, L., Gluckman, J.L. and Stambrook, P.J.(1997)Overexpression and amplification of glutathione S-transferase pi gene in head and neck squamous cell carcinomas. Clin Cancer Res, 3, 111-114.
Weng, M.W., Hsiao, Y.M., Chiou, H.L., Yang, S.F., Hsieh, Y.S., Cheng, Y.W., Yang, C.H. and Ko, J.L.(2005)Alleviation of benzo[a]pyrene-diolepoxide-DNA damage in human lung carcinoma by glutathione S-transferase M2. DNA Repair(Amst), 4, 493-502.
Wheeler, J.B., Stourman, N.V., Thier, R., Dommermuth, A., Vuilleumier, S., Rose, J.A., Armstrong, R.N. and Guengerich, F.P.(2001)Conjugation of haloalkanes by bacterial and mammalian glutathione transferases: mono- and dihalomethanes. Chem Res Toxicol, 14, 1118-1127.
Wolterbeek, A.P., Schoevers, E.J., Rutten, A.A. and Feron, V.J.(1995)A critical appraisal of intratracheal instillation of benzo[a]pyrene to Syrian golden hamsters as a model in respiratory tract carcinogenesis. Cancer Lett, 89, 107-116.
Woo, R.A. and Poon, R.Y.(2004)Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation. Genes Dev, 18, 1317-1330.
Xu, C., Li, C.Y. and Kong, A.N.(2005)Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch Pharm Res, 28, 249-268.
Yamashita, S., Tsujino, Y., Moriguchi, K., Tatematsu, M. and Ushijima, T.(2006)Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2''-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci, 97, 64-71.