進階搜尋


 
系統識別號 U0026-0812200911423895
論文名稱(中文) C/EBPα 在rifampin誘發CYP3A4中所扮演的角色
論文名稱(英文) Role of C/EBPα in the CYP3A4 induction by rifampin
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 93
學期 2
出版年 94
研究生(中文) 鄭竹晏
研究生(英文) Chu-Yen Cheng
學號 s2692113
學位類別 碩士
語文別 中文
論文頁數 87頁
口試委員 口試委員-呂增宏
口試委員-簡偉明
指導教授-黃金鼎
中文關鍵字 報告基因 
英文關鍵字 rifampin  C/EBPα  CYP3A4 
學科別分類
中文摘要   細胞色素P450為含鐵基質的單氧化酵素,參與了許多外來物質的代謝。人類的細胞色素3A家族包含四個成員:3A4、3A5、3A7以及3A43。其中3A4的含量最多,並且參與目前使用藥物約百分之五十的代謝。
  有些外來分子為PXR(pregnane X receptor)的特異性配體,可以透過PXR反應序列而誘發CYP3A4表現。PXR反應序列在人類CYP3A4基因中,是在轉錄起始區前端約一百五十個鹼基對的位置,以及上游約八千個鹼基對的促進組中。最近的研究(Drug Metab Dispos.2004; 32:525-535)指出:破壞CYP3A4近端啟動區中C/EBPα、Sp1、HNF3以及PXR的結合區域,會改變外來分子(rifampicin,metyrapone,clotrimazole, phenobarbital)對於CYP3A4的活化能力。這是首度論證認為:外來分子可能藉由非PXR的路徑誘發CYP3A4的表現。因此,本研究在探討:在rifampin調控CYP3A4中,C/EBPα所扮演的角色。
  為了研究CYP3A4的調控,我們將近端啟動區(-444 ~ +53)建構於luciferase報告基因之前。在HepG2細胞中大量表現C/EBPα,增加了CYP3A4啟動區的活性;在LS174T細胞中則不然。在HepG2以及LS174T細胞中,轉染C/EBPα會減弱rifampin對CYP3A4的誘發作用。在凝膠電泳遷移力分析中,一段C/EBPα的固有結合序列,會減弱HepG2細胞核萃取液和PXR反應序列的結合;同時C/EBPα抗體會對於此結合產生supershift。以反轉錄-聚合酶連鎖反應以及西方點墨法加以研究,證實在HepG2細胞中C/EBPα會正向調控CYP3A4的表現。然而,因為過量的C/EBPα會佔據PXR反應區域,而使C/EBPα減弱了rifampin對CYP3A4的誘發作用。在LS174T細胞中,C/EBPα對於CYP3A4的表現不具作用。由於C/EBPα會對內生性PXR與PXR反應區域的結合產生拮抗作用,所以事實上過度表現C/EBPα會減弱CYP3A4的表現。這些結果顯示在調控CYP3A4中,C/EBPα會與PXR反應序列產生交互作用。因為C/EBPα在發炎反應中扮演重要角色,因此這些結果也許具有臨床意義。
英文摘要  The cytochrome P450 3As (CYP3As) are heme-containing monooxygenases involved in the metabolism of various foreign compounds. Four CYP3A genes have been described in human, CYP3A4, CYP3A5, CYP3A7 and CYP3A43. CYP3A4 is the most abundant and metabolizes approximately 50% of the drugs currently in use.
 Some xenobiotics are specific ligands of PXR (pregnane X receptor) and induce CYP3A4 through the PXRE motif. In human CYP3A4, PXR binding site motifs are present at approximately -150bp and also within an enhancer module some 8kb upstream of the transcription start site. The recent study (Drug Metab Dispos.2004; 32:525-535)showed that disruption of the C/EBPα, Sp1, HNF3, and PXR binding sites within the CYP3A4 proximal promoter altered the activation by the xenobiotic (rifampicin, metyrapone, clotrimazole, and phenobarbital). It is the first demonstration that xenobiotics may induce CYP3A4 gene expression through PXR- independent pathways. The role of C/EBPα in the rifampicin-mediated regulation of the CYP3A4 gene is examined in my study.
 Proximal region of promoter (-444~+53) was constructed with the luciferase reporter gene to assess the regulation of CYP3A4. Over-expression of C/EBPαincreased CYP3A4 promoter activity in HepG2 cells, but not in LS174T cells. Inducibility of CYP3A4 by rifampin was decreased by transfeciton of C/EBPα in both cells. In EMSA, binding of PXRE to HepG2 nuclear extracts was decreased by a consensus C/EBPα binding sequence. C/EBPα antibody caused a supershift of the C/EBPα-PXRE binding. RT-PCR and Western blots further confirmed that C/EBPα positively regulated CYP3A4 expression in HepG2 cells. Inductive effect of rifampin is however diminished by C/EBPα. Because the excessive C/EBPα also occupied PXRE. In LS174T cells, C/EBPα has no effect on CYP3A4 expression. Because of the antagonism at PXRE with endogenous PXR, C/EBPα overexpression in fact decreased CYP3A4 expression. These observations support the interaction between C/EBPα and PXRE in CYP3A4 regulation. Because C/EBPα is one of inflammatory reactants, this finding may have clinical implications.
論文目次 表目錄………………………………………………………………….. I
圖目錄………………………………………………………………….. II
中文摘要……………………………………………………………….. 1
英文摘要……………………………………………………………….. 3
縮寫檢索表……………………………………………………………... 5
第一章 緒論…………………………………………………………... 6
第二章 實驗材料…………………………………………………….. 15
第三章 實驗方法…………………………………………………….. 23
第四章 實驗結果…………………………………………………….. 48
第五章 總結與討論………………………………………………….. 53
參考文獻……………………………………………………………….. 57
附表………………………………………………………………….... 68
附圖………………………………………………………………….... 73
自述………………………………………………………………….... 87
參考文獻 Antonson P, and Xanthopoulos KG. (1995) Molecular cloning, sequence and expression patterns of the human gene encoding CCAAT/enhancer binding protein alpha (C/EBP alpha). Biochem Biophys Res Commun 215:106–113

Anttila S, Hukkanen J, Hakkola J, Stjernvall T, Beaune P, Edwards RJ, Boobis AR, Pelkonen O, Raunio H. (1997) Expression and localization of CYP3A4 and CYP3A5 in human lung. Am J Respir Cell Mol Biol 16: 242-249

Baertschi SW, Raney KD, Shimada T, Harris TM, Guengerich FP. (1989) Comparison of rates of enzymatic oxidation of aflatoxin B1, aflatoxin G1, and sterigmatocystin and activities of the epoxides in forming guanyl-N7 adducts and inducing different genetic responses. Chem Res Toxicol 2: 114-2

Barwick JL, Quattrochi LC, Mills AS, Potenza C, Tukey RH, Guzelian PS. (1996) Trans-species gene transfer for analysis of glucocorticoid-inducible transcriptional activation of transiently expressed human CYP3A4 and rabbit CYP3A6 in primary cultures of adult rat and rabbit hepatocytes. Mol Pharmacol 50:10–16

Beaune PH, Umbenhauer DR, Bork RW, Lloyd RS, and Guengerich FP. (1986) Isolation and sequence determination of a cDNA clone related to human cytochrome P-450 nifedipine oxidase. Proc Natl Acad Sci U.S.A. 83:8064-8068

Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Backman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A. (1998) Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci U.S.A. 95:12208–12213

Birkenmeier EH, Gwynn B, Howard S, Jerry J, Gordon JI, Lanschulz WH, McKnight SL. (1989) Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. Gene Dev 3: 1146-1156

Blumberg B, Sabbagh Jr W, Juguilon H, Bolado Jr J, van Meter CM, Ong ES, Evans RM. (1998) SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12:3195–3205

Bombail V, Taylor K, Gordon Gibson G, and Plant N. (2004) Role of Sp1, C/EBPα , HNF3, and PXR in the basal- and xenobiotic-mediated regulation of the CYP3A4 gene. Drug Metab Dispos 32: 525-535

Burgess-Beusse BL and Darlington GJ. (1998) C/EBPalpha is critical for the neonatal acute-phase response to inflammation. Mol Cell Biol 18:7269–7277

Burk O, Wojnowski L. (2004) Cytochrome P450 3A and their regulation. Naunyn Schmiedebergs Arch Pharmacol 369:105-124

Cao Z, Umek RM, McKnight SL. (1991) Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-Ll cells. Gene Dev 5: 1538-1552

Caraco Y. (1998) Genetic determinants of drug responsiveness and drug interactions. Ther Drug Monit 20: 517-524

Cereghini S. (1996) Liver-enriched transcription factors and hepatocyte differentiation. FASEB J 10:267–282

Dai D, Tang J, Rose R, Hodgson E, Bienstock RJ, Mohrenweiser HW and Goldstein JA. (2001) Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J. Pharmacol Exp Ther 299: 825-831

Daniel W Nebert, David W Russell. (2002) Clinical importance of the cytochromes P450. Lancet 360:1155-1162

Domanski TL, Finta C, Halpert JR, Zaphiropoulos PG. (2001) cDNA of cloning and initial characterization of CYP3A43, a novel human cytochrome P450. Mol Pharmacol 59(2):386-392

Evans AM. (2000) Influence of dietary components on the gastrointestinal metabolism and transport of drugs. Ther Drug Monit 22:131–136

Evans WE, Relling MV. (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286:487-491

Fey GH, Hocke GM, Wilson DR, et al. (1994) Cytokine and the Acute Phase Response of the Liver. In: Arias IM, Boyer JL, Fausto N, Jakoby WB, Schachter DA, Shafritz DA. The Liver: Biology and Pathobiology. Third Ed. New York: Raven Press, 11343

Finta C, Zaphiropoulos PG. (2000) The human cytochrome P450 3A locus. Gene evolution by capture of downstream exons. Gene 260: 13-23

Friedman AD, Landschulz, McKnight SL. (1989) CCAAT/enhancer binding protein activates the promoter of the serum albumin gene in cultured hepatoma cells. Gene Dev 3: 1314-1322

Gellner K, Eiselt R, Hustert E, Arnold H, Koch I, Haberl M, Deglmann CJ, Burk O, Buntefuss D, Escher S, Bishop C, Koebe HG, Brinkmann U, Klenk HP, Kleine K, Meyer UA, Wojnowski L. (2001) Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics 11:111–121

Gonzalez FJ, Schmid BJ, Umeno M, Mcbride OW, Hardwick JP, Meyer UA, Gelboin HV, and Idle JR. (1988) Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA 7:79-86

Giguere V. (1999) Orphan Nuclear Receptors: From Gene to Function Endocrine Reviews 20: 689–725

Gonzalez FJ. (1990) Molecular genetics of the P450 superfamily. Pharmacol Ther 45: 1-38

Gonzalez F and Lee Y. (1996) Constitutive expression of hepatic cytochrome P450 genes. FASEB J 10:1112–1117

Goodwin B, Hodgson E, Liddle C. (1999) The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 56:1329–1339

Goodwin B, Hodgson E, D’Costa DJ, Robertson GR, Liddle C. (2002) Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor. Mol Pharmacol 62: 359–365

Guengerich FP. (1997) Role of cytochrome P450 enzymes in drug-drug interactions. Adv Pharmacol 43:7–35

Guengerich FP. (1999)Cytochrome P450 3A4: Regulation and Role in Drug Metabolism. Annu Rev Pharmacol Toxicol 39: 1-17

Hashimoto H, Toide K, Kitamura R, Fujita M, Tagawa S, Itoh S, Kamataki T. (1993) Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control. Eur J Biochem 218:585–595

Hsieh KP, Yu Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP, and Huang JD. (2001) Novel Mutations of CYP3A4 in Chinese. Drug Metab Dispos 29: 268-273

Hustert E, Zibat A, Presecan-Siedel E, Eiselt R, Mueller R, Fuss C, Brehm I, Brinkmann U, Eichelbaum M, Wojnowski L, Burk O. (2001) Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4. Drug Metab Dispos 29: 1454-1459

Itoh S, Yanagimoto T, Tagawa S, Hashimoto H, Kitamura R, Nakajima Y, Okochi T, Fujimoto S, Uchino J, Kamataki T. (1992) Genomic organization of human fetal specific P-450IIIA7 (cytochrome P-450HFLa)-related gene(s) and interaction of transcriptional regulatory factor with its DNA element in the 5’ flanking region. Biochem Biophys Acta 1130: 133-138

Jones SA, Moore LB, Shenk JL, Wisely GB, Hamilton GA, McKee DD, Tomkinson NC, LeCluyse EL, Lambert MH, Willson TM, Kliewer SA, Moore JT. (2000) The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol 14:27–39

Jover R, Bort R, Gomez-Lechon MJ, and Castell JV. (1998) Re-expression of C/EBP alpha induces CYP2B6, CYP2C9 and CYP2D6 genes in Hep G2 cells. FEBS Lett 431:227–230

Kitada M, Kamataki T, Itahashi K, Rikihisa T, Kanakubo Y. (1987) P-450 HFLa, a form of cytochrome P-450 purified from human fetal livers, is the 16 alpha-hydroxylase of dehydroepiandrosterone 3-sulfate. J Biol Chem 262: 13534-13537

Kleinbloesem CH, van Brummelen P, Faber H, Danhof M, Vermeulen NP, Breimer DD. (1984) Variability in nifedipine pharmacokinetics and dynamics: a new oxidation polymorphism in man. Biochem Pharmacol 33: 3721-3724

Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, Perlmann T, Lehmann JM. (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92:73–82

Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 102:1016–1023

Li AP, Kaminski DL, Rasmussen A. (1995) Substrates of human hepatic cytochrome P450 3A4. Toxicology 104:1-8

Lin WJ, Li J, Lee YF, Yeh SD, Altuwaijri S, Ou JH, Chang C. (2003) Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4. J Biol Chem 278:9353-60

Lin YS, Lockwood GF, Graham MA, Brian WR, Loi CM, Dobrinska MR Shen DD, Watkins PB, Wilkinson GR, Kharasch ED, Thummel KE. (2001) In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration. Pharmacogenetics 11:781-791

Lin YS, Dowling ALS, Quigley SD, Farin FM, Zhang J, Lamba J, Schuetz EG, Thummel KE. (2002) Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol 62: 162-172

Lown KS, Kolars JC, Thummel KE, Barnett JL, Kunze KL, Wrighton SA, Watkins PB. (1994) Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test. Drug Metab Dispos 22: 947-955

Lown KS, Thummel KE, Benedict PE, Shen DD, Turgeon DK, Berent S, Watkins PB. (1995) The erythromycin breath test predicts the clearance of midazolam. Clin Pharmacol Ther 57: 16-24

Masuhiro N, Hiroshi Y, Hiroki Y, Shinsaku N, and Tetsuo S. (2003) Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by High-sensitivity Real-Time reverse transcription PCR. YAKUGAKU ZASSHI 123:369-375

Mischoulon D, Rana B, Bucher NLR, Farmer SR. (1992) Growth-dependent inhibition of CCAAT enhancer-binding protein (C/EBPalpha) gene expression during hepatocyte proliferation in the regenerating liver and in culture. Mol Cell Biol 12: 2553-2560

Mueller CR, Maire P Schibler U. (1990) DBP a liver-enriched transcriptional activator, is expressed late in ontogeny and its tissue specificity is determined posttranscriptionally. Cell 61: 279-290

Muranda M, Del Solar JA, Jorquera C, Saavedra L, Pemjean I. (1973) Megaloblastic anemia caused by pyrazinamide. Rev Med Chil 101: 151-154

Murray GI, Pritchard S, Melvin WT, Burke MD. (1995) Cytochrome P450 CYP3A5 in the human anterior pituitary gland. FEBS Lett 364: 79-82

Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, Gunsalus IC, Nebert DW. (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6: 1-42

Ourlin JC, Jounaidi Y, Maurel P, and Vilarem MJ. (1997) Role of the liver-enriched transcription factors C/EBP alpha and DBP in the expression of human CYP3A4 and CYP3A7. J Hepatol 26(S2):54–62.

Ramji DP, and Foka P. (2002) CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J 365:561–575

Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB. (1998) Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 90:1225-1229

Rodriguez-Antona C, Bort R, Jover R, Tindberg N, Ingelman-Sundberg M, Gomez-Lechon MJ, Castell JV. (2003) Transcriptional regulation of human CYP3A4 basal expression by CCAAT enhancer-binding protein alpha and hepatocyte nuclear factor-3gamma. Mol Pharmacol 63:1180–1189

Sata F, Sapone A, Elizondo G, Stocker P, Miller VP, Zheng W, Raunio H, Crespi CL, Gonzalez FJ. (2000) CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity. Clin Pharmacol Ther 67: 48-56

Schuetz EG, Schuetz JD, Grogan WM, Naray-Fejes-Toth A, Fejes-Toth G, Raucy J, Guzelian P, Gionela K, Watlington CO. (1992) Expression of cytochrome P450 3A in amphibian, rat, and human kidney. Arch Biochem Biophys 294: 206-214

Schuetz JD, Beach DL, Guzelian PS. (1994) Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver. Pharmacogenetics 4: 11-20

Shimada T, Guengerich FP. (1989) Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver. Proc Natl Acad Sci U S A. 86: 462-465

Spurdle AB, Goodwin B, Hodgson E, Hopper JL, Chen X, Purdie DM, McCredie MR, Giles GG, Chenevix-Trench G, Liddle C. (2002) The CYP3A4*1B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer. Pharmacogenetics 12: 355-366

Spurr NK, Gough AC, Stevenson K, and Wolf CR. (1989) The human cytochrome P450 CYP3A locus: assignment to cytochrome 7q22-qter. Hum Genet 81:171-174

Tateishi T, Watanabe M, Moriya H, Yamaguchi S, Sato T, Kobayashi S. (1999) No ethnic difference between Caucasian and Japanese hepatic samples in the expression frequency of CYP3A5 and CYP3A7 proteins. Biochem Pharmacol 57:935– 939

Thompson PD, Jurutka PW, Whitfield GK, Myskowski SM, Eichhorst KR, Dominguez CE, Haussler CA, Haussler MR. (2002) Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements. Biochem Biophys Res Commun 299:730–738

Thummel KE, Wilkinson GR. (1998) In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 38:389–430

Thummel KE, Brimer C, Yasuda K, Thottassery J, Senn T, Lin Y, Ishizuka H, Kharasch E, Schuetz J, Schuetz E. (2001) Transcriptional control of intestinal cytochrome P-4503A by 1alpha,25- dihydroxy vitamin D3. Mol Pharmacol 60:1399–1406

Tirona RG, Lee W, Leake BF, Lan LB, Cline CB, Lamba V, Parviz F, Duncan SA, Inoue Y, Gonzalez FJ, Schuetz EG, Kim RB. (2003) The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med 9:220–224

Toshifumi A, Shigeru Y, David JW, David PL, Urs AM, Volker F, Rachel T, Tadanobu I, Werner K, Harry VG, and Frank JG. (1989) Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene proguct that is differentially expressed in adult human liver. J Biol Chem 264:10388-10395

Van Ooij C, Snyder RC, Paeper SW, Duester G. (1992) Temporal expression of the human alcohol dehydrogenase gene family during liver development correlates with differential promoter activation by hepatocyte nuclear factor 1, CCAAT/ enhancer-binding protein , liver activator protein, and D-element- binding protein. Mol Cell Biol 12: 3023-3031

Wandel CW, Witte JS, Hall JM, Stein CM, Wood AJ, and Wilkinson GR. (2000) CYP3A activity in Afican-American and European-American men: population differences and functional effect of the CYP3A4*1B 5’-promoter region polymorphism. Clin Pharmacol Ther 68:82-91

Wang ND, Finegold MJ, Bradley A, Ou CN, Abdelsayed SV, Wilde MD, Taylor LR, Wilson DR, and Darlington GJ. (1995) Impaired energy homeostasis in C/EBP alpha knockout mice. Science 269:1108–1112

Waxman DJ, Attisano C, Guengerich FP, Lapenson DP. (1988) Human liver microsomal steroid metabolism: identification of the major microsomal steroid hormone 6 beta-hydroxylase cytochrome P-450 enzyme. Arch Biochem Biophys 263: 424-436

Westlind A, Löfberg L, Tindberg N, Andersson TB, and Ingelman-Sundberg M. (1999) Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5’-upstream regulatory region. Biochem. Biophys. Res. Commun. 259:201-205

Westlind A, Malmebo S, Johansson I, Otter C, Andersson TB, Ingelman- Sundberg M, Oscarson M. (2001) Cloning and tissue distribution of a novel human cytochrome p450 of the CYP3A subfamily, CYP3A43. Biochem Biophys Res Commun 281: 1349–1355

Wick N, Schleiffer A, Huber LA, Vietor I. (2004) Inhibitory effect of TIS7 on Sp1-C/EBPalpha transcription factor module activity. J Mol Biol 336:589-595

Wilkinson GR. (1996) Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm 24:475–490

Williams SC, Cantwell CA, Johnson PE. (1991) A family of C/EBP related proteins capable of forming covalently linked leucine zipper dimers in vitro. Gene Dev 5: 1553-67.

Wrighton SA, Ring BJ, Watkins PB, and Van Den BM. (1989) Identification of a polymorphically expressed member of human cytochrome P-450III family. Mol. Pharmacol. 36:97-105

Wrighton SA, Brian WR, Sari MA, Iwasaki M, and Guengerich FP. (1990) Studies on the expression and metabolic capabilities of human liver cytochrome P-450 A5 (HLp3). Mol. Pharmacol. 38:207-213
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2006-08-30起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2006-08-30起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw