人类羰基还原酶基因CBR1和DCXR的克隆及其编码蛋白的功能研究
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摘要
肝癌为我国常见的恶性肿瘤之一，其死亡率在消化系统恶性肿瘤中列第三位，寻找和鉴定肝癌相关基因并研究它们的生物学功能，将有助于揭示肝癌的发生机制并为药物治疗提供选择药物的依据。羰基还原酶(CBRs，EC 1．1．1．184)参与还原包括醌在内的各种羰基化合物，在解除细胞内的正常代谢产物或外源性化合物的毒性效应方面起着重要的作用。目前已发现的人羰基还原酶基因共有4个，它们分别为CBR1、DCXR、CBR3和CBR4。我室1998年利用同源克隆策略得到其中的DCXR基因，GenBank登录号为AF139841，本文主要是对CBR1和DCXR基因编码蛋白的功能及其可能的临床应用价值进行分析。
本研究首先检查了这两个基因的表达状况。结果显示，人体16种组织的CBR1和DCXR基因在肝脏中的表达量明显高于其它各组织，尤其是DCXR基因在肝脏中的表达丰度远远高于其它各组织，这可能与肝脏的解毒功能有关。然而，34对肝癌和癌旁组织的Northern Blot、RT-PCR及免疫组织化学检测结果却显示，CBR1和DCXR基因在肝癌组织中的的表达水平显著低于正常对照，这间接反映出肝组织癌变时解毒功能受到严重损害，也可能反映了肝癌的发病机制与肝脏解毒功能有某种关联。
我们对原核表达的重组CBR1和DCXR蛋白进行了还原酶活性分析，发现它们都能特异性地还原典型的醌类底物9，10—菲醌和醛酮类底物吲哚满二酮，具有羰基还原酶活性。当酶促反应体系pH值为6.2左右时，酶催化底物的活性最强，这与相关文献的报道相一致。为了判断它们在肝癌中显著下调表达的特征是否可用于指导临床用药，我们分析了这二种酶对17种抗癌药物的代谢能力。结果发现，CBR1和DCXR能特异性地代谢抗癌药物长春新碱(VCR)，沙尔威辛(SALVICIN)和表没食子儿茶素没食子酸酯(EGCG)。
然而，尽管CBR1对EGCG显示脱氢酶活性，但对于仅在B环结构上与EGCG分子存在差异的表儿茶素没食子酸酯(ECG)分子，我们却检测不到这种脱氢酶活性，据此我们推测CBR1催化EGCG的部位可能是B环焦酚型结构。应用EGCG进行诱导细胞凋亡和细胞周期阻滞的实验，结果发现：当药物浓度达到20ug／ml时，转染了CBRl基因的SK-HEP-1实验组细胞凋亡发生的比例(3.40％)明显低于仅转入了空载体的SK-HEP-1对照组细胞(15.52％)(p＜0.01)。阻滞在G1期的细胞也是实验组(60.42％)少于对照组(72.63％)(p＜0.01)。提示CBR1基因的表达产物具有拮抗EGCG诱导细胞凋亡和诱导细胞G1期阻滞的作用。细胞毒性实验证实，在30ug／ml浓度EGCG药物作用下，稳定转染了CBR1基因的肝癌细胞SK-HEP-1(25％)对EGCG的耐受性是转染了空载体的对照组细胞(9.1％)的2.7倍(p＜0.05)，但是对5—氟尿嘧啶的耐受性未发生明显变化(p＞0.05)，提示细胞对EGCG药物敏感性的降低与CBR1基因的随机插入无关。此外，还发现在50ug／ml浓度EGCG药物作用时，CBR1表达量较高的肝癌细胞株HepG2(51.98％)对EGCG的耐受性显著高于CBR1表达量较低的肝癌细胞株Hep-3B(21.82％)(p＜0.05)。提示EGCG特异性诱导肿瘤细胞凋亡(而不影响正常细胞)的表观性状可能与在正常成人肝组织中大量表达而在肝癌组织中下调表达的CBR1蛋白对EGCG的灭活作用有关，这对临床用药可能具有重要的指导意义。
进一步的研究还显示，在肝癌细胞株FOCUS中稳定表达DCXR蛋白能使细胞对DNR和VCR的敏感性显著降低(p＜0.05)。在人宫颈癌细胞Hela中稳定表达DCXR蛋白也能使细胞对这两种药物的敏感性降低(p＜0.05)。DCXR蛋白能在临床剂量范围内拮抗常用抗癌药物柔红霉素和长春新碱的毒性的实验结果提示，DCXR蛋白可作为研究醛酮类抗肿瘤药物药效的一种新的标志物。
我们的这项研究表明，CBR1和DCXR是两种在肝脏中高丰度表达的解毒蛋白，它们在肝细胞发生癌变时表达锐减。它们的代谢底物虽然都是含羰基的醛酮类及醌类化合物，但对各种具有上述结构的抗癌药物的底物特异性却存在较大差别。CBR1对表没食子儿茶素没食子酸酯(EGCG)的代谢作用最强，在肝癌细胞内大量表达CBR1能引起细胞对EGCG药物耐受性提高；而DCXR则对柔红霉素(DNR)和长春新碱(VCR)的代谢作用强，且在细胞内大量表达DCXR能引起细胞对这两种药物的耐受性的提高。二者对不具有上述结构的5—氟尿嘧啶的代谢作用均很弱。这些初步的研究结果提示，肝癌组织中CBR1和DCXR两个基因的表达丰度的变化可作为临床医生选用抗癌药物的一种参考指标。
Carbonyl reductases (EC 1.1.1.184, CRs), belonging to the superfamily of oxidoreductases, are mostly monomeric and cytosolic enzymes with broad substrate specificity for many endogenous and xenobiotic carbonyl compounds. So far there are four human carbonyl reductases have been recognized, including CBR1, DCXR, CBR3 and CBR4. DCXR was cloned by homogenous screening strategy and submitted to Genebank with accession No. AF139841. In this thesis, we study the characteristics of CBR1 and DCXR and their association with Hepatic Cellular Carcinoma (HCC).
Northern blot analysis of human CBR1 and DCXR was carried out on multiple tissue samples from 16 adult human tissues to confirm theirs natural existence and tissue distribution. CBR1 was found to be 1.65 kb in length and abundant in liver, kidney, brain, middle in heart, pancreas, placenta, lung, while little in other tissues. DCXR was 1.35 kb in length and abundant in liver, kidney, heart, pancreas, and middle in brain, placenta, lung, spleen, thymus, but little in peripheral blood lymphocyte and colon. Then the transcriptional expression pattern of DCXR in liver cancer was detected and found to be commonly down-regulated in liver cancer tissues. DCXR protein was expressed in E. coli and purified by chromatography. The purified protein was used to immunize rabbits and polyclonal antibody was obtained. With the immunohistochemistry method by the polyclonal antibody, DCXR was found obviously expressed lower in the HCC tissues than in the normal liver tissues. It figures out some clues of the relationship between DCXR and HCC and provides some useful indications that the decreased DCXR expression might be a marker of liver cancer.
Recombinant CBR1 and DCXR were purified from E. coli to detect their enzyme activity. Both DCXR and CBR1 were found to show reductase activity on isatin and 9,10-phenanthrenedione with NADPH as cofactor at fittest pH value of about 6.2. Then we screened 17 anti-cancer drugs to identify the new substrates of CBR1 and DCXR. The results indicated that daunorubicin, vincristine, salvicine and (-)-epigallocatechin gallate (EGCG) were found to be the substrates of CBR1 and DCXR and the later three have not been reported so far. Based on the molecular structure comparing, we found that only EGCG was with epicatechin gallate that was confirmed to promote cell apoptosis. Therefore, we speculated the enzyme catalyzing
position located at the galloyl structure on the B ring of epigallocatechin gallate, which was important for cell apoptosis induction. The hepatic carcinoma cells (SK-HEP-1 cells) stably transfected with CBR1 showed dramatic insensitivity to EGCG induced apoptosis, suggesting that high expressed CBR1 might be used as molecular marker to exclude EGCG treatment for HCC.
Likes CBR1, DCXR can catalyze daunorubicin, vincristine, salvicine and EGCG. These anti-cytotoxicity roles of DCXR, protecting cells from daunorubicin, vincristine and EGCG, have been assessed by forced expression of DCXR through stable transfection of cDNA encoding DCXR in FOCUS cells and Hela cells. Cells highly expressing DCXR showed increased resistance to daunorubicin and vincristine but EGCG compared to their parent cells when measured with MTS cyto-toxicity assays (p<0.05). This is the first report that DCXR can metabolize anti-cancer drugs and decrease the chemosensitivity of cancer cells to daunorubicin and vincristine. The cloning of human DCXR genes may initiate further investigation of the carbonyl reductase's role in tumor chemotherapy, and is important for study of pharmacological deactivation of drugs with carbonyl group.
本研究首先检查了这两个基因的表达状况。结果显示，人体16种组织的CBR1和DCXR基因在肝脏中的表达量明显高于其它各组织，尤其是DCXR基因在肝脏中的表达丰度远远高于其它各组织，这可能与肝脏的解毒功能有关。然而，34对肝癌和癌旁组织的Northern Blot、RT-PCR及免疫组织化学检测结果却显示，CBR1和DCXR基因在肝癌组织中的的表达水平显著低于正常对照，这间接反映出肝组织癌变时解毒功能受到严重损害，也可能反映了肝癌的发病机制与肝脏解毒功能有某种关联。
我们对原核表达的重组CBR1和DCXR蛋白进行了还原酶活性分析，发现它们都能特异性地还原典型的醌类底物9，10—菲醌和醛酮类底物吲哚满二酮，具有羰基还原酶活性。当酶促反应体系pH值为6.2左右时，酶催化底物的活性最强，这与相关文献的报道相一致。为了判断它们在肝癌中显著下调表达的特征是否可用于指导临床用药，我们分析了这二种酶对17种抗癌药物的代谢能力。结果发现，CBR1和DCXR能特异性地代谢抗癌药物长春新碱(VCR)，沙尔威辛(SALVICIN)和表没食子儿茶素没食子酸酯(EGCG)。
然而，尽管CBR1对EGCG显示脱氢酶活性，但对于仅在B环结构上与EGCG分子存在差异的表儿茶素没食子酸酯(ECG)分子，我们却检测不到这种脱氢酶活性，据此我们推测CBR1催化EGCG的部位可能是B环焦酚型结构。应用EGCG进行诱导细胞凋亡和细胞周期阻滞的实验，结果发现：当药物浓度达到20ug／ml时，转染了CBRl基因的SK-HEP-1实验组细胞凋亡发生的比例(3.40％)明显低于仅转入了空载体的SK-HEP-1对照组细胞(15.52％)(p＜0.01)。阻滞在G1期的细胞也是实验组(60.42％)少于对照组(72.63％)(p＜0.01)。提示CBR1基因的表达产物具有拮抗EGCG诱导细胞凋亡和诱导细胞G1期阻滞的作用。细胞毒性实验证实，在30ug／ml浓度EGCG药物作用下，稳定转染了CBR1基因的肝癌细胞SK-HEP-1(25％)对EGCG的耐受性是转染了空载体的对照组细胞(9.1％)的2.7倍(p＜0.05)，但是对5—氟尿嘧啶的耐受性未发生明显变化(p＞0.05)，提示细胞对EGCG药物敏感性的降低与CBR1基因的随机插入无关。此外，还发现在50ug／ml浓度EGCG药物作用时，CBR1表达量较高的肝癌细胞株HepG2(51.98％)对EGCG的耐受性显著高于CBR1表达量较低的肝癌细胞株Hep-3B(21.82％)(p＜0.05)。提示EGCG特异性诱导肿瘤细胞凋亡(而不影响正常细胞)的表观性状可能与在正常成人肝组织中大量表达而在肝癌组织中下调表达的CBR1蛋白对EGCG的灭活作用有关，这对临床用药可能具有重要的指导意义。
进一步的研究还显示，在肝癌细胞株FOCUS中稳定表达DCXR蛋白能使细胞对DNR和VCR的敏感性显著降低(p＜0.05)。在人宫颈癌细胞Hela中稳定表达DCXR蛋白也能使细胞对这两种药物的敏感性降低(p＜0.05)。DCXR蛋白能在临床剂量范围内拮抗常用抗癌药物柔红霉素和长春新碱的毒性的实验结果提示，DCXR蛋白可作为研究醛酮类抗肿瘤药物药效的一种新的标志物。
我们的这项研究表明，CBR1和DCXR是两种在肝脏中高丰度表达的解毒蛋白，它们在肝细胞发生癌变时表达锐减。它们的代谢底物虽然都是含羰基的醛酮类及醌类化合物，但对各种具有上述结构的抗癌药物的底物特异性却存在较大差别。CBR1对表没食子儿茶素没食子酸酯(EGCG)的代谢作用最强，在肝癌细胞内大量表达CBR1能引起细胞对EGCG药物耐受性提高；而DCXR则对柔红霉素(DNR)和长春新碱(VCR)的代谢作用强，且在细胞内大量表达DCXR能引起细胞对这两种药物的耐受性的提高。二者对不具有上述结构的5—氟尿嘧啶的代谢作用均很弱。这些初步的研究结果提示，肝癌组织中CBR1和DCXR两个基因的表达丰度的变化可作为临床医生选用抗癌药物的一种参考指标。
Carbonyl reductases (EC 1.1.1.184, CRs), belonging to the superfamily of oxidoreductases, are mostly monomeric and cytosolic enzymes with broad substrate specificity for many endogenous and xenobiotic carbonyl compounds. So far there are four human carbonyl reductases have been recognized, including CBR1, DCXR, CBR3 and CBR4. DCXR was cloned by homogenous screening strategy and submitted to Genebank with accession No. AF139841. In this thesis, we study the characteristics of CBR1 and DCXR and their association with Hepatic Cellular Carcinoma (HCC).
Northern blot analysis of human CBR1 and DCXR was carried out on multiple tissue samples from 16 adult human tissues to confirm theirs natural existence and tissue distribution. CBR1 was found to be 1.65 kb in length and abundant in liver, kidney, brain, middle in heart, pancreas, placenta, lung, while little in other tissues. DCXR was 1.35 kb in length and abundant in liver, kidney, heart, pancreas, and middle in brain, placenta, lung, spleen, thymus, but little in peripheral blood lymphocyte and colon. Then the transcriptional expression pattern of DCXR in liver cancer was detected and found to be commonly down-regulated in liver cancer tissues. DCXR protein was expressed in E. coli and purified by chromatography. The purified protein was used to immunize rabbits and polyclonal antibody was obtained. With the immunohistochemistry method by the polyclonal antibody, DCXR was found obviously expressed lower in the HCC tissues than in the normal liver tissues. It figures out some clues of the relationship between DCXR and HCC and provides some useful indications that the decreased DCXR expression might be a marker of liver cancer.
Recombinant CBR1 and DCXR were purified from E. coli to detect their enzyme activity. Both DCXR and CBR1 were found to show reductase activity on isatin and 9,10-phenanthrenedione with NADPH as cofactor at fittest pH value of about 6.2. Then we screened 17 anti-cancer drugs to identify the new substrates of CBR1 and DCXR. The results indicated that daunorubicin, vincristine, salvicine and (-)-epigallocatechin gallate (EGCG) were found to be the substrates of CBR1 and DCXR and the later three have not been reported so far. Based on the molecular structure comparing, we found that only EGCG was with epicatechin gallate that was confirmed to promote cell apoptosis. Therefore, we speculated the enzyme catalyzing
position located at the galloyl structure on the B ring of epigallocatechin gallate, which was important for cell apoptosis induction. The hepatic carcinoma cells (SK-HEP-1 cells) stably transfected with CBR1 showed dramatic insensitivity to EGCG induced apoptosis, suggesting that high expressed CBR1 might be used as molecular marker to exclude EGCG treatment for HCC.
Likes CBR1, DCXR can catalyze daunorubicin, vincristine, salvicine and EGCG. These anti-cytotoxicity roles of DCXR, protecting cells from daunorubicin, vincristine and EGCG, have been assessed by forced expression of DCXR through stable transfection of cDNA encoding DCXR in FOCUS cells and Hela cells. Cells highly expressing DCXR showed increased resistance to daunorubicin and vincristine but EGCG compared to their parent cells when measured with MTS cyto-toxicity assays (p<0.05). This is the first report that DCXR can metabolize anti-cancer drugs and decrease the chemosensitivity of cancer cells to daunorubicin and vincristine. The cloning of human DCXR genes may initiate further investigation of the carbonyl reductase's role in tumor chemotherapy, and is important for study of pharmacological deactivation of drugs with carbonyl group.
引文
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39. Hirotami O., Yoshiyuki M., Yoshihiro D., et al. Reduction of drug ketones by dihydrodiol dehydrogenease, carbonyl reductase and aldehyde reductase of human liver. Biochem Pharmacol. 1995, 50: 221-227
40. Holleran J. L., Fourcade J., Egorin M. J., et al. In vitro metabolism of the phosphatidylinositol 3-kinase inhibitor, wortmannin, by carbonyl reductase. Drug Metab Dispos. 2004, 32(5): 490-6.
41. Breyer-Pfaff U, Nill K. Carbonyl reduction of naltrexone and dolasetron by oxidoreductases isolated from human liver cytosol. J Pharm Pharmacol. 2004, 56(12): 1601-6.
42. Shimoda K, Shibasaki M, Inaba T, et al. Carbonyl reduction of timiperone in human liver cytosol. Pharmacol Toxicol. 1998, 83(4): 164-8.
43. Gonzalez B., Akman S., Doroshow J., et al. Protection against daunorubicin cytotoxicity by expression of a cloned human carbonyl reductase cDNA in k562 leukemia-cells. Cancer Res, 1995, 55 (20): 4646-4650
44. Ahmad N., Gupta S., Mukhtar H. Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappaB in cancer cells versus normal cells. Arch Biochem Biophys, 2000, 376: 338-346
45. Wang Y. C, Bachrach U. The specific anti-cancer activity of green tea (-)-epigallocatechin-3-gallate (EGCG). Amino Acids, 2002,22(2): 131-43.
46. Brusselmans K., De Schrijver E., Heyns W., et al. Epigallocatechin-3-gallate is a potent natural inhibitor of fatty acid synthase in intact cells and selectively induces apoptosis in prostate cancer cells. Int J Cancer, 2003, 106(6): 856-62.
47. Paul B., Hayes C. S., Kim A., et al. Elevated polyamines lead to selective induction of apoptosis and inhibition of tumorigenesis by (-)-epigallocatechin-3-gallate (EGCG) in ODC/Ras transgenic micel. Carcinogenesis, 2004 Sep 16; [Epub ahead of print]
48. Li H. C, Yashiki S., Sonoda J, et al. Green tea polyphenols induce apoptosis in vitro in peripheral blood T Lymphocytes of adult T-cell leukemia Patients. 2000, Jpn J Cancer Res, 91: 34-40
1. H. Oritani, Y. Deyashiki, T. Nakayama, et al., Arch. Biochem. Biophys. 292 (1992) 539-547.
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5. M. Wada, M. Kataoka, H. Kawabata, et al. Biosci. Biotechnol. Biochem. 62 (1998) 280-285.
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10. N. Iwata, N. Inazu, T. Satoh. J. Biochem. 107 (1990) 209-212.
11. B. Wermuth, Prostaglandins 44 (1992) 5-9.
12. M. Krook, D. Ghosh, W. Duax, eral. FEBS Lett. 322 (1993) 139-142.
13. H. Jomvall, B. Persson, M. Krook, et al. Biochemistry 34 (1995) 6003-6013.
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15. N. Tanaka, T. Nonaka, M. Nakanishi et al. J. Biochem. (Tokyo) 118 (1995) 871-873.
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17. R. Felsted, N. Bachur, in: F. J. DiCarol (Ed.), Drug Metabolism Reviews, Marcel Dekker, New York, 1980, pp. 1-60.
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29. M. Nakanishi, Y. Deyashiki, K. Ohshima et al. Eur. J. Biochem. 228 (1995) 381-387.
30. Y.S. Park, C.W. Heizmann, B. Wermuth, et al. Biochem. Biophys. Res. Commun. 175(1991)738-744.
31. T. Iino, M. Tabata, S. Takikawa, Archives Of Biochemistry And Biophysics, 416 (2003): 180-187
32. T. Iino, S.I. Takikawa, T. Yamamoto, et al. Arch. Biochem. Biophys. 373 (2000) 442-446.
33. El-Kabbani, S. Ishikura, C. Darmanin, Proteins-Structure Function and Bioinformatics, 55 (2004): 724-732
34. N. Tanaka, T. Nonaka, KT. Nakamura, et al. Current Organic Chemistry, 5(2001): 89-111
35. S. Ishikura, T. Isaji, N. Usami, et al. A Chemico-Biological Interactions, 143 (2003): 543-550
36. C. Filling, K. D. Berndt, J. Benach, et al., Journal Of Biological Chemistry, 277(2002): 25677-25684
37. M. A. Sciotti, B. Wermuth, Chemico-Biological Interactions. 130(2001): 871-878 Sp. Iss. SI
38. Y. W. Huang, I. Pineau, H. .J. Chang, et al., Molecular Endocrinology, 15 (2001): 2010-2020
39. E. Toft, M. Soderstrom, M.B. Ahlberg, et al., Biochem. Biophys. Res. Commun. 201 (1994)149-154.
40. H. Chung, J. Fried, J. Jarabak, Prostaglandins 33 (1987) 391-402.
41. H. Jornvall, B. Persson, M. Krook, et al., Biochemistry 34 (1995) 6003-6013.
42. G.L. Forrest, S. Akman, S. Krutzik, et al., Biochim. Biophys. Acta. 1048 (1990) 149-155
43. M. Krook, D. Ghosh, R. Stromberg, et al., Proc. Natl. Acad. Sci. USA 90 (1993) 502-506.
44. B. Wermuth, K.M. Bohren, E. Ernst, FEBS Lett. 335 (1993) 151-154.
45. B. Wermuth, G Mader-Heinemann, E. Ernst, et al., Eur. J. Biochem.228 (1995) 473-479.
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38. Ahmed N. K., Felsted R. L. Bachur N. R. Heterogeneity of anthracycline antibiotics carbonyl reductases in mammalian livers. Biochem Pharmacol, 1978, 27:2713-2719
39. Hirotami O., Yoshiyuki M., Yoshihiro D., et al. Reduction of drug ketones by dihydrodiol dehydrogenease, carbonyl reductase and aldehyde reductase of human liver. Biochem Pharmacol. 1995, 50: 221-227
40. Holleran J. L., Fourcade J., Egorin M. J., et al. In vitro metabolism of the phosphatidylinositol 3-kinase inhibitor, wortmannin, by carbonyl reductase. Drug Metab Dispos. 2004, 32(5): 490-6.
41. Breyer-Pfaff U, Nill K. Carbonyl reduction of naltrexone and dolasetron by oxidoreductases isolated from human liver cytosol. J Pharm Pharmacol. 2004, 56(12): 1601-6.
42. Shimoda K, Shibasaki M, Inaba T, et al. Carbonyl reduction of timiperone in human liver cytosol. Pharmacol Toxicol. 1998, 83(4): 164-8.
43. Gonzalez B., Akman S., Doroshow J., et al. Protection against daunorubicin cytotoxicity by expression of a cloned human carbonyl reductase cDNA in k562 leukemia-cells. Cancer Res, 1995, 55 (20): 4646-4650
44. Ahmad N., Gupta S., Mukhtar H. Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappaB in cancer cells versus normal cells. Arch Biochem Biophys, 2000, 376: 338-346
45. Wang Y. C, Bachrach U. The specific anti-cancer activity of green tea (-)-epigallocatechin-3-gallate (EGCG). Amino Acids, 2002,22(2): 131-43.
46. Brusselmans K., De Schrijver E., Heyns W., et al. Epigallocatechin-3-gallate is a potent natural inhibitor of fatty acid synthase in intact cells and selectively induces apoptosis in prostate cancer cells. Int J Cancer, 2003, 106(6): 856-62.
47. Paul B., Hayes C. S., Kim A., et al. Elevated polyamines lead to selective induction of apoptosis and inhibition of tumorigenesis by (-)-epigallocatechin-3-gallate (EGCG) in ODC/Ras transgenic micel. Carcinogenesis, 2004 Sep 16; [Epub ahead of print]
48. Li H. C, Yashiki S., Sonoda J, et al. Green tea polyphenols induce apoptosis in vitro in peripheral blood T Lymphocytes of adult T-cell leukemia Patients. 2000, Jpn J Cancer Res, 91: 34-40
1. H. Oritani, Y. Deyashiki, T. Nakayama, et al., Arch. Biochem. Biophys. 292 (1992) 539-547.
2. B. Wermuth, Prog. Clin. Biol. Res. 174 (1985) 209-230.
3. M. E. Baker, Biochem. J. 300 (1994) 605-607.
4. U. C. Oppermann, G. Nagel, I. Belai, et al. Chem. Biol. Interact. 114 (1998) 211-224.
5. M. Wada, M. Kataoka, H. Kawabata, et al. Biosci. Biotechnol. Biochem. 62 (1998) 280-285.
6. G. Guan, M. Tanaka, T. Todo, G. et al. Biochem. Biophys. Res. Commun. 255 (1999) 123-128.
7. N. Iwata, N. Inazu, S. Hara, et al. Biochem. Pharmacol. 45 (1993) 1711-1714.
8. N. K. Ahmed, R. L. Felsted, N. R. Bachur. Biochem. Pharmacol. 27 (1978) 2713-2719.
9. M. Tanaka, S. Ohno, S. Adachi, et al. J. Biol. Chem. 267 (1992) 13451-13455.
10. N. Iwata, N. Inazu, T. Satoh. J. Biochem. 107 (1990) 209-212.
11. B. Wermuth, Prostaglandins 44 (1992) 5-9.
12. M. Krook, D. Ghosh, W. Duax, eral. FEBS Lett. 322 (1993) 139-142.
13. H. Jomvall, B. Persson, M. Krook, et al. Biochemistry 34 (1995) 6003-6013.
14. N. Tanaka, T. Nonaka, T. Tanabe, et al. Biochemistry 35 (1996) 7715-7730.
15. N. Tanaka, T. Nonaka, M. Nakanishi et al. J. Biochem. (Tokyo) 118 (1995) 871-873.
16. J. M. Jez, M.J. Bennett, B. P. Schlegel, et al. Biochem. J. 326 (1997) 625-636.
17. R. Felsted, N. Bachur, in: F. J. DiCarol (Ed.), Drug Metabolism Reviews, Marcel Dekker, New York, 1980, pp. 1-60.
18. B. Wermuth, J.Biol. Chem. 256(1981) 1206-1213.
19. R.W. Schieber, S. Frank, Ghisla, Eur..!. Biochem. 206 (1992) 491-502.
20. L. Wermuth, K. Platts, A. Seidel et al. Biochem. Pharmacol. 35 (1986) 1277-1282.
21. H. Ohara, Y. Miyabe, Y. Deyashiki et al. Biochem. Pharmacol. 50 (1995) 221-227.
22. B. Wermuth, G. Mader-Heinemann, E. Ernst, et al. Eur. J. Biochem. 228 (1995) 473-479.
23. N. Inazu, Y. Nagashima, T. Satoh, et al. J. Biochem. (Tokyo) 115 (1994) 991-999.
24. N. Iwata, N. Inazu, T. Satoh, Prog. Clin. Biol. Res. 290 (1989) 307-321.
25. L. Skalova, M. Nobilis, B. Szotakova, et al. Biochemical Pharmacology, 64 (2002): 297-305
26. Y. Imamura, A. Ryu, T. Koga, et al. J. Biochem. Tokyo 119 (1996) 648-652.
27. Y. Imamura, T. Migita, M. Otagiri, et al. J. Biochem. (Tokyo) 125 (1999) 41-47.
28. Y. Imamura, T. Migita, M. Anraku, et al. Biol. Pharm. Bull. 22 (1999) 731-733.
29. M. Nakanishi, Y. Deyashiki, K. Ohshima et al. Eur. J. Biochem. 228 (1995) 381-387.
30. Y.S. Park, C.W. Heizmann, B. Wermuth, et al. Biochem. Biophys. Res. Commun. 175(1991)738-744.
31. T. Iino, M. Tabata, S. Takikawa, Archives Of Biochemistry And Biophysics, 416 (2003): 180-187
32. T. Iino, S.I. Takikawa, T. Yamamoto, et al. Arch. Biochem. Biophys. 373 (2000) 442-446.
33. El-Kabbani, S. Ishikura, C. Darmanin, Proteins-Structure Function and Bioinformatics, 55 (2004): 724-732
34. N. Tanaka, T. Nonaka, KT. Nakamura, et al. Current Organic Chemistry, 5(2001): 89-111
35. S. Ishikura, T. Isaji, N. Usami, et al. A Chemico-Biological Interactions, 143 (2003): 543-550
36. C. Filling, K. D. Berndt, J. Benach, et al., Journal Of Biological Chemistry, 277(2002): 25677-25684
37. M. A. Sciotti, B. Wermuth, Chemico-Biological Interactions. 130(2001): 871-878 Sp. Iss. SI
38. Y. W. Huang, I. Pineau, H. .J. Chang, et al., Molecular Endocrinology, 15 (2001): 2010-2020
39. E. Toft, M. Soderstrom, M.B. Ahlberg, et al., Biochem. Biophys. Res. Commun. 201 (1994)149-154.
40. H. Chung, J. Fried, J. Jarabak, Prostaglandins 33 (1987) 391-402.
41. H. Jornvall, B. Persson, M. Krook, et al., Biochemistry 34 (1995) 6003-6013.
42. G.L. Forrest, S. Akman, S. Krutzik, et al., Biochim. Biophys. Acta. 1048 (1990) 149-155
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