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122 巻, 9 号
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Reviews
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小林 道也2002 年 122 巻 9 号 p. 607-614
発行日: 2002/09/01
公開日: 2003/02/18
ジャーナル フリーThis article reviewed the transport mechanism of polycationic compounds across rat intestinal and renal cell membranes. The inside-negative diffusion potential stimulated the initial uptake of dicationic compounds into intestinal brush-border membrane vesicles, and a good correlation was observed between lipophilicity and the amount of diffusion potential-dependent transport of the dications. On the other hand, tri- and tetracationic compounds were not affected by the diffusion potential because of their much lower lipophilicity. The membrane surface potential affected to the transport of polycationic compounds, similar to monocationic compounds. Therefore it appears that the membrane surface potential plays a common role in the transport of mono- and polycationic compounds across cell membranes. On the intestinal basolateral membrane, it was found that there was a Na+/putrescine symporter. This recognized dicationic compounds and transported them from the blood into intestinal cells. This transporter did not recognize spermine and spermidine. Furthermore, we found a novel transport system, a Na+/spermine antiporter, on the rat renal brush-border membrane. This transporter recognized aliphatic polycation, which has more than four amino groups, and actively secreted spermine and trientine into the renal proximal tubules in vitro and in vivo. However, this transporter did not recognize trientine-copper complex. These results are useful for the prediction of the intestinal absorption and renal excretion of polyamine derivatives.
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川原 裕之2002 年 122 巻 9 号 p. 615-624
発行日: 2002/09/01
公開日: 2003/02/18
ジャーナル フリーThe ubiquitin-dependent proteolytic pathway is thought to be one of the vital systems for cellular regulations, including control of the cell cycle, differentiation and apoptosis. In this pathway, poly-ubiquitinated proteins are selectively degraded by the 26S proteasome, a multisubunit proteolytic machinery. Recognition of the poly-ubiquitin chain by the 26S proteasome should be a key step leading to the selective degradation of target proteins, and the Rpn10 subunit of the 26S proteasome has been shown to preferentially bind the poly-ubiquitin chain in vitro. We previously reported that the mouse Rpn10 mRNA family is generated from a single gene by developmentally regulated, alternative splicing. To determine whether such alternative splicing mechanisms occur in organisms other than the mouse, we searched for Rpn10 isoforms in various species. Here we summarize the gene organization of the Rpn10 in lower species and provide evidence that the competence for generating all distinct forms of Rpn10 alternative splicing has expanded through evolution. Some of the Rpn10 family genes were found to be expressed in distinct developmental stages, suggesting that they have distinct functions during embryogenesis. For example, Rpn10c and Rpn10e were exclusively expressed at specific developmental stages and in specific tissues, while Rpn10a was expressed constitutively. Our experimental results indicate that the respective Rpn10 proteins possess distinct roles in the progression of development. Furthermore, some of the Rpn10 variants specifically interacted with important developmental regulators.
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森 博美2002 年 122 巻 9 号 p. 625-636
発行日: 2002/09/01
公開日: 2003/02/18
ジャーナル フリーQuick detection of substances causing acute poisoning is often difficult. There is a need for methods that allow rapid detection of pesticides causing acute poisoning, which is often severe and has a high mortality rate, for quick diagnosis and appropriate treatment. The aim of this study was therefore to develop rapid and simple analytical methods for detecting acute poisoning-inducing substances in samples of stomach contents, returned gastric lavage solution, serum, or urine using an analytical device that can be used in the field as well as in pharmaceutical divisions and emergency medical units. We first examined the effectiveness of a screening method using TLC and then the effectiveness of HPLC equipped with a photo-diode array detector (HPLC-DAD) for qualitative and quantitative measurements. In the former technique, we were able to develop a rapid and simple screening method by adjusting the TLC plate and development solvent. In the latter technique, we were able to establish rapid and accurate methods for qualitative and quantitative measurements by using a column-switching technique in which a sample is injected directly into the column without pretreatment. Results of tests using actual samples obtained from patients with acute poisoning showed that the time required for detection using these techniques (less than 1h) was much shorter than that required using conventional techniques. The use of these techniques should reduce the mortality rate in cases of acute poisoning, since physicians would be able to receive prompt advice regarding diagnosis, prognosis, and treatment methods. We have also designed a practical system for analysis of acute poisoning-inducing pesticides.
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田中 宏幸2002 年 122 巻 9 号 p. 637-642
発行日: 2002/09/01
公開日: 2003/02/18
ジャーナル フリーBronchial asthma is considered to be a chronic airway inflammatory disease, characterized by airway obstruction, airway eosinophilic inflammation, and airway hyperresponsiveness (AHR) to a variety of stimuli. AHR is thought to be an important symptom, because the severity of the disease is generally correlated with the degree of AHR. Recent clinical studies have demonstrated the involvement of airway inflammation in the development of allergen-induced AHR, although, the mechanism of allergen-induced AHR has not been fully elucidated and remains controversial. In vivo animal models might provide important information on this point. We have established a mouse model of allergic asthma, which is characterized by airway eosinophilia, IgE production, T helper type 2 (Th2) cytokine production in the airway, and AHR, and investigated the role of inflammatory cells and functional molecules. Results from gene-knockout and mutant mice demonstrated the involvement of T cells, mast cells, prostanoids, and Th2 cytokines including interleukin (IL)-4 and IL-5 in the development of allergen-induced airway inflammation and AHR. In contrast, treatment with anti-IL-4 monoclonal antibody (mAb) or anti-IL-5 mAb during allergen inhalation did not inhibit allergen-induced AHR, although the combination of these mAbs clearly inhibited the enhanced responsiveness. These data indicate that it is a better strategy for control of the disease to inhibit or suppress multifunctional molecules like corticosteroids rather than to inhibit a single factor, because bronchial asthma is a multifactorial disease.
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東 満美2002 年 122 巻 9 号 p. 643-649
発行日: 2002/09/01
公開日: 2003/02/18
ジャーナル フリーPituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide first isolated from ovine hypothalamic tissue. This peptide stimulates adenylate cyclase activation. However, few details were known of the function of this peptide on stimulus-secretion coupling in neuronal cells. The authors have investigated the role of PACAP on catecholamine biosynthesis and secretion using cultured bovine adrenal chromaffin cells as a model for catecholamine-containing neurons. PACAP38, the 38-amino acid form of PACAP, increased cAMP formation in bovine adrenal chromaffin cells. In addition, PACAP38 increased [Ca2+]i associated with PI turnover and Ca2+ influx into the cells. The synthesis of catecholamine and the phosphorylation of tyrosine hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis, stimulated by the maximal effective concentration of dibutyryl cAMP or a high concentration (56 mM) of K+ were further enhanced by PACAP38. Thus PACAP38 stimulated the pathway of catecholamine biosynthesis mainly by both activation of cAMP- and Ca2+-dependent protein kinases. On catecholamine secretion from the cells, the effect of PACAP38 was markedly potentiated by addition of ouabain, an inhibitor of Na+/K+ ATPase. This markedly potentiated secretion was greatly reduced with Na+ omitted-sucrose medium. PACAP38 increased 22Na+ influx into the cells treated with ouabain. Thus PACAP38 with ouabain stimulated catecholamine secretion by accumulation of intracellular Na+, resulting in an increase in Ca2+ influx. These results indicate that the neuropeptide PACAP has an important role in stimulus-secretion coupling in adrenal chromaffin cells.
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金田 幸, 梶村 芳雄2002 年 122 巻 9 号 p. 651-671
発行日: 2002/09/01
公開日: 2003/02/18
ジャーナル フリーWe isolated four strains of bacteria producing antifungal antibiotics from the rhizosphere of garlic with basal rot caused by the plant pathogenic fungal strain Fusarium oxysporum. Among them, Bacillus subtilis FR-2 was found to produce new antifungal antibiotics, named bacillopeptins A, B, and C. Their structures have been determined by 1D and 2D NMR and MS experiments, and amino acid analysis coupled with chiral HPLC, to be cyclic lipopeptides each containing a long-chain β-amino acid. Another bacterial strain, Bacillus polymyxa KT-8, was shown to produce new antifungal antibiotics named fusaricidins A, B, C, and D which are more potent than bacillopeptins in their antimicrobial activity. The structures of the fusaricidins have been elucidated similarly as bacillopeptins to be cyclic hexadepsipeptides all containing 15-guanidino-3-hydroxypentadecanoic acid as a side chain. Fusaricidins strongly inhibit the growth of various kinds of fungi and moreover surprisingly show strong inhibitory activity against Gram-positive bacteria such as Staphylococcus aureus or Micrococcus luteus.
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Regular Articles
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岡本 安弘, 山本 孫兵衛, 安藝 初美2002 年 122 巻 9 号 p. 673-679
発行日: 2002/09/01
公開日: 2003/02/18
ジャーナル フリーLipophilic ion-pair complexes of 3-dl-α-tocopherylcarbonyl-1-n-alkyl-pyridinium-cromolyn (TAP-CG) were designed to enhance the percutaneous absorption of cromolyn (CG), and the effect of n-alkyl chainlength of the ion-pair complexes on the CG permeation through hairless mouse skin was evaluated in vitro. The permeation rates of CG were examined in isopropyl myristate (IPM) suspension using static Keshany-Chien type diffusion cells at 32°C. The permeation parameters, steady-state flux, diffusion coefficient, partition coefficient between skin and IPM, and permeability coefficient were determined. Steady-state fluxes of CG increased linearly with the increasing n-alkyl chain-length of TAP-CG, and 3-dl-α-tocopherylcarbonyl-1-n-hexyl-pyridinium-cromolyn (THP-CG) produced the highest CG flux (0.62 ± 0.11nmol·cm-2·h-1), which was 14-fold greater than that of CG·Na in IPM suspension and more than 480-fold greater than that of CG·Na in aqueous solution due to increasing lipophilicity. In the case of TAP-CG with longer n-alkyl chainlength than THP-CG, however, the steady-state fluxes of CG decreased due to the high molecular weight and/or the high lipophilicity of the ion-pair complexes. It is suggested that lipophilic ion-pair complexes, especially THP-CG, are effective in absorption of cromoglicate through the skin. The results would be useful for studies on the role of each counterion in the lipophilic ion-pair complexes.
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鈴木 理恵, 大津 史子, 矢野 玲子, 榊原 仁作, 稲垣 員洋2002 年 122 巻 9 号 p. 681-693
発行日: 2002/09/01
公開日: 2003/02/18
ジャーナル フリーObjectives: The purpose of this study was to develop, implement, and assess estimation procedures to prevent adverse drug reactions (ADRs), especially drug-induced metabolic disorders, based on the subjective symptoms (complaints) of patients. Methods: Our own database called CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information System) was started in 1987 and now contains ca. 23,000 case reports of ADRs. We extracted 264 cases of drug-induced metabolic disorders from CARPIS, such as hyperglycemia, hypoglycemia, and hypokalemia. Evaluation scores were created based on the subjective symptoms and the backgrounds of these patients. The scores were applied to the 264 cases to demonstrate their efficiency in estimation of ADRs. Results: The evaluation scores estimated ADRs as follows: 39.6% of the 96 hyperglycemia cases, 53.6% of the 84 hypoglycemia cases, and 59.5% of the 84 hypokalemia cases. The validity measures of the evaluation scores were estimated to be as follows: for hyperglycemia sensitivity (SE)=39.6%, specificity (SP)=99.0%, predictive value of positive test (PVP)=97.4%, positive likelihood ratio (PLR)=39.6, and negative likelihood ratio (NLR)=0.61; for hypoglycemia, SE=53.6%, SP=93.0%, PVP=86.5%, PLR=7.7 and NLR= 0.50; and for hypokalemia, SE=59.5%, SP=99.0%, PVP=98.0%, PLR=59.5, and NLR=0.41. Conclusions: The proposed evaluation scores are a reliable estimation method to detect ADRs related to drug-induced metabolic disorders. The scores should be incorporated into the integrated ADR estimation system available at a Web site our institution is developing, along with other evaluation scores of drug-induced liver disorders, extrapyramidal symptoms, and leakopenia, and druy eruptions.
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石原 三也, 本間 真人, 久能 英子, 渡邊 真知子, 幸田 幸直2002 年 122 巻 9 号 p. 695-701
発行日: 2002/09/01
公開日: 2003/02/18
ジャーナル フリーThe intestinal bacteria, Eubacterium sp. and Bifidobacterium sp., participate in the metabolism of active kampo-ingredients, glycyrrhizin (GL), sennoside (SEN) and baicalin (BL). Since antibiotics and bacterial preparations, Bifidobacterium longum (LAC-B®), Clostridium butyricum (MIYA-BM®), and Streptococcus faecalis (BIOFERMIN®), affect the bacterial population in intestinal bacterial flora, metabolism of the active kampo-ingredients in the bacterial flora may be altered by their combined administration. We investigated 1199 prescriptions including kampo-medicines for 308 patients. Combination use of kampo-medicines with antibiotics and bacterial preparations occurred with 7% and 10% of the kampo-prescription, respectively. Most antibiotics have activity against intestinal bacteria, except that cephems and macrolides are not active against to E. coli. This means that antibiotics may lower the metabolism of GL, SEN and BL when administered in combination. On the other hand, it is also highly possible that bacterial preparations increase the number of Eubacterium sp. and Bifidobacterium sp., resulting in enhanced metabolism of GL and SEN when they are used concomitantly with kampo-medicines. The present results suggested that the drug interactions of kampo-medicines with antibiotics and bacterial preparations should be confirmed in clinical studies.
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Notes
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Ryota SAITO, Kallol K. GHOSH, Kazuo HARADA, Akira KATOH原稿種別: Note
2002 年 122 巻 9 号 p. 703-705
発行日: 2002/09/01
公開日: 2003/02/18
ジャーナル フリーThree 3-hydroxymonoazine- and three N-hydroxydiazine-type heterocycles were tested whether they act as artificial siderophores toward Aureobacterium flavescens JG-9 (ATCC No. 25091). Among them, 1-hydroxy-3,5,6-trimethyl-2(1H)-pyrazinone (3) showed the highest growth-promotion activity comparable to desferrioxamine B (DFB), a natural trihydroxamate siderophore, at 48.5μM or above, followed by 1-hydroxy-5,6-dimethyl-2(1H)-pyrazinone (2), 1-hydroxy-4,6-dimethyl-2(1H)-pyrimidinone (1), and 3-hydroxy-2-methyl-1-phenyl-4(1H)-pyridinone (6), while 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone (5) did not show the bioactivity. These results are the first examples of N-hydroxydiazine-type heterocycles acting as artificial siderophores for A. flavescens JG-9.
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