YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
116 巻, 7 号
選択された号の論文の5件中1~5を表示しています
  • 今川 正良
    1996 年 116 巻 7 号 p. 505-518
    発行日: 1996/07/25
    公開日: 2008/05/30
    ジャーナル フリー
    Rat glutathione transferase P (GST-P) is expressed at low levels in the normal liver but becomes highly expressed in hyperplastic nodules and in hepatocellular carcinomas during chemical hepatocarcinogenesis. To understand the regulation mechanisms of this gene, we have characterized the 5'-flanking region and have found that GST-P gene is regulated by at least two elements : one is a strong enhancer and the other is a silencer. GST-P enhancer I (GPEI), located at -2.5 Kb, consists of two TPA-responsive element (TRE)-like sequences that are palindromically oriented with 3 bp in between. It is well known that TRE is activated by two nuclear oncogenes, c-Jun and c-Fos. Although GPEI is trans-activated by these oncogenes, it is also active in F9 embryonal carcinoma cells that lack c-Jun protein, suggesting that it can function with some trans-activator other than AP-1 (c-Jun/c-Fos heterodimer). Indeed, another protein is identified from the F9 nuclear extract. We have also identified a silencer element at 300 bp upstream from the cap site. There are several cis-elements in this region and at least three trans-acting factors bind to these elements. We purified SF-A (silencer factor A) which binds to several regions in this silencer, and determined the partial amino acid sequence. Interestingly, SF-A seemed to be a related protein to NF1 (nuclear factor 1) which is an activator for the transcription and DNA replication. Another factor SF-B (silencer factor B) has been cloned and found to be the same as LIP (liver inhibitory protein) which is a competitor for LAP (liver activator protein), both are from the same gene designated as C/EBPβ. By transfection analysis using GAL4 DNA binding domain we found LIP is not only a competitor but a direct repressor. In the normal liver, another C/EBP family member, C/EBPα also acts as a negative regulator, and this expression decreases during hepatocarcinogenesis, resulting in the loss of silencer function. We carried out the carcinogenesis experiments using transgenic rats harboring a chloramphenicol acetyltransferase (CAT) reporter gene with -2900 to +59 of the GST-P gene. Liver foci and nodules produced by chemical carcinogens were found to express high levels CAT activity by both CAT assay and immunohistochemical study, while normal liver cells did not express any CAT activity. These results demonstrate that the GST-P gene is trans-activated locus-independently during rat hepatocarcinogenesis. Moreover, the similar results were obtained using transgenic rats carrying GPEI-CAT, indicating that GPEI is an important cis-element for activation of GST-P gene during hepatocarcinogenesis.
  • 高倉 喜信
    1996 年 116 巻 7 号 p. 519-532
    発行日: 1996/07/25
    公開日: 2008/05/30
    ジャーナル フリー
    With a rapid progress in biotechnology, a variety of endogenous macromolecular substances have become a novel class of therapeutic agents. This review will focus on the development of delivery systems for macromolecular drugs. Current status and future perspectives in this research field are reviewed mainly based on the results obtained in our laboratory. First of all, we studied pharmacokinetic characteristics of macromolecules in relation to their physicochemical properties such as molecular weight and electric charge. Based on this information, we first developed macromolecular prodrugs as a delivery system for low molecular weight drugs. An antitumor antibiotic, mitomycin C (MMC) were covalently conjugated with dextran and various types of macromolecular prodrug of MMC were developed for tumor targeting. Secondly, delivery systems for protein drugs such as soybean trypsin inhibitor, uricase, and recombinant superoxide dismutase (SOD) were developed. In particular, successful targeting of SOD to the liver, kidney and blood circulation was achieved by chemical modification of the protein drug. Finally, we have been trying to develop delivery systems for nucleic acid drugs involving antisense oligonucleotides and plasmid DNA. Prior to the development of delivery systems, we found that the pharmacokinetics of the nucleic acid drugs are decided by their physicochemical properties as polyanions even if these materials contain genetic information. Several approaches were tested to control the in vivo behavior of the oligonucleotides and plasmid DNA based on the finding. Thus, we have established the strategy for rational design of delivery systems for various types of macromolecular drugs based on the pharmacokinetic considerations. This methodology can be a formidable tool for the development of clinically applicable macromolecular drugs.
  • 清水 當尚, 宇野 準, 伊藤 継孝, 増田 義信, 黒川 美貴雄
    1996 年 116 巻 7 号 p. 533-547
    発行日: 1996/07/25
    公開日: 2008/05/30
    ジャーナル フリー
    Zonisamide (1, 2-benzisoxazole-3-methanesulfonamide, AD-810) is a broad spectrum antiepileptic drug which has been launched in Japan and South Korea. It lacks the ureide structure included in most of the existing antiepileptic drugs. Zonisamide was synthesized by the sulfonation and the successive amination of 1, 2-benzisoxazole-3-acetic acid in a very poor yield. After several efforts to optimaize the compound, zonisamide was selected based on the balance of the efficacy and safety. The yield was greatly improved by the development of new synthetic routes. Zonisamide suppressed maximal electroshock seizures in mice, rats, rabbits and dogs. Its therapeutic plasma concentration range between anticonvulsant and neurotoxic effects was much wider than that of the existing antiepileptic drugs. In electroencephalographic studies on animal models of epilepsy, zonisamide, like phenytoin and carbamazepine, restricted the spread or propagation of seizures and, like sodium valproate, it suppressed the epileptogenic focus activity. Zonisamide was effective in several kindling models. In clinical studies, zonisamide exerted the efficacy against partial seizures (simple, complex, secondarily generalized seizures) and some generalized seizures (tonic-clonic, tonic, atypical absence seizures) that were comparable to that of carbamazepine and sodium valproate, respectively. Zonisamide was also effective in monotherapy. The adverse effects related with zonisamide were mainly drowsiness, ataxia, loss of appetite and gastrointestinal symptoms. Serious adverse effects which may be life-threatening have not been reported.
  • 青柳 高明
    1996 年 116 巻 7 号 p. 548-565
    発行日: 1996/07/25
    公開日: 2008/05/30
    ジャーナル フリー
    In living organisms a large number of enzymes are working in complicated networks to express various biological functions. In order to analyze such functions from various aspects, specific enzyme inhibitors are likely to become useful tools. They are also useful for the studies of reaction mechanisms and analysis of three-dimensional structures of enzymes. Moreover, they are of great value in elucidating disease processes and seem to have usefulness in treatment of various diseases. Searching for inhibitors in culture filtrate of microbes, we discovered many substances which specifically inhibit various enzymes such as endopeptidases, exopeptidases, glycosidases, lipases, an so forth. These inhibitors have lowmolecular-weights and unique structures. We found significant activities of exopeptidases, alkaline phosphatases, esterases, and so forth, on surface membranes of various mammalian cells. Searching for specific inhibitors against these cell surface enzymes, we have discovered many interesting inhibitors. These inhibitors proved to bind to the cellular surface and to modify the functions of cells involved in immune responses. Thus the studies on these enzyme inhibitors may well afford important keys to understand various aspect of biological phenomena and diseases : inflammation, immune response, hypertension, hyperlipemia, diabetes, Alzheimer's disease, carcinogenesis, metastasis, viral infection, autoimmune diseases, and so forth. Because of their interesting pharmacological activities, some of the inhibitors are now under clinical evaluation for their uses as medical drugs. Enzyme inhibitors seems to propose a new promising field of science.
  • 日野 亨
    1996 年 116 巻 7 号 p. 566-586
    発行日: 1996/07/25
    公開日: 2008/05/30
    ジャーナル フリー
    A historical development of the chemistry of cyclic tautomer of tryptophan is reviewed. The cyclic tautomer of tryptophan, pyrrolo [2, 3-b] indole-2-carboxylic acid, was prepared by dissolving N-methoxycarbonyltryptophan ester derivatives in 85% phosphoric acid or trifluoroacetic acid. The cyclic tautomer can be reverted to the indolic form with a dilute acid. The cyclic tautomer is an aniline derivative and the enamine reactivity of the indole ring in tryptophan is protected. The electrophilic substitution and oxidation of these cyclic tautomers opened a new method to prepare 5-substituted and/or 6-substituted tryptophan derivatives such as 5-bromo-, 5-hydroxy, and 6-methoxy-tryptophans. The formation and reactions of cyclic tautomers of diketopiperazines containing tryptophan and 3-indoleacetamide are also discussed. Some indole alkaloids having substituents at the benzene ring such as fumitremorgins, flustramine B, and eudistomines were synthesized by the use of these reactions. Furthermore, enantioselective alkylations of the carbanion at the 2-position of the cyclic tautomer established a new route to optically pure α-substituted tryptophans. The 2, 3-dehydro derivative of the cyclic tautomer is an α, β-unsaturated ester and was found to be a good precursor of optically pure β-substituted tryptophans. The 3a-position of the cyclic tautomer is a benzylic position and subjected to radical reactions to give 3a-substituted-pyrroloindoles.
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