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その他
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中道, 範隆 ; Nakamichi, Noritaka
概要:
取得学位：博士(薬学)，学位授与番号：博甲第719号，学位授与年月日：平成17年3月22日
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| 2.
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Sugiyama, Chie ; Nakamichi, Noritaka ; Ogura, Masato ; Honda, Eriko ; Maeda, Sayaka ; Taniura, Hideo ; Yoneda, Yukio
概要:
金沢大学大学院自然科学研究科分子作用学<br />Activation of ionotropic glutamate (Glu) receptors, such as N-methyl-d-aspartate receptors, is
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shown to modulate the gene transcription mediated by the transcription factor activator protein-1 (AP1) composed of Fos and Jun family proteins in the brain, while little attention has been paid to the modulation of AP1 expression by metabotropic Glu receptors (mGluRs). In cultured rat cortical neurons, where constitutive expression was seen with all groups I, II and III mGluR subtypes, a significant and selective increase was seen in the DNA binding activity of AP1 120 min after the brief exposure to the group II mGluR agonist (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV) for 5 min. In cultured rat cortical astrocytes, by contrast, a significant increase was induced by a group I mGluR agonist, but not by either a group II or III mGluR agonist. The increase by DCG-IV was significantly prevented by a group II mGluR antagonist as well as by either an intracellular Ca2+ chelator or a voltage-sensitive Ca2+ channel blocker, but not by an intracellular Ca2+ store inhibitor. Moreover, DCG-IV significantly prevented the increase of cAMP formation by forskolin in cultured neurons. Western blot analysis revealed differential expression profiles of Fos family members in neurons briefly exposed to DCG-IV and NMDA. Prior or simultaneous exposure to DCG-IV led to significant protection against neuronal cell death by NMDA. These results suggest that activation of the group II mGluR subtype would modulate the gene expression mediated by AP1 through increased intracellular Ca2+ levels in cultured rat cortical neurons. © 2007.
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論文
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Nakamichi, Noritaka ; Yoneda, Yukio
概要:
金沢大学大学院自然科学研究科分子作用学<br />In contrast to other ionotropic glutamate receptors, N-methyl-d-aspartate (NMDA) receptor chann
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els are rather stable after the simulation. Brief exposure to NMDA at 50 μM rapidly increased the fluorescence intensity for increased intracellular free Ca2+ levels in a reversible- and concentration-dependent manner in rat cortical neurons cultured for 3-15 days in vitro (DIV), while EC50 values were significantly decreased in proportion to cellular maturation from 3 to 15 DIV. Although a constant increase was persistently seen in the fluorescence throughout the sustained exposure to NMDA for 60 min irrespective of the cell maturation from 3 to 15 DIV, the second brief exposure for 5 min resulted in a less efficient increase in the fluorescence than that found after the first brief exposure for 5 min in a manner dependent on intervals between the two repetitive brief exposures. In vitro maturation significantly shortened the interval required for the reduced responsiveness to the second brief exposure, while in immature neurons prolonged intervals were required for the reduced responsiveness to the second brief exposure to NMDA. Moreover, brief exposure to NMDA led to a marked decrease in immunoreactivity to extracellular loop of NR1 subunit in cultured neurons not permeabilized in proportion to the time after washing. These results suggest that cellular maturation would facilitate the desensitization process to repeated stimulation by NMDA, without markedly affecting that to sustained stimulation, through a mechanism related to the decreased number of NMDA receptors expressed at cell surfaces in cultured rat cortical neurons. © 2006 Elsevier Ltd. All rights reserved.
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Fujita, Ken-ichi ; Sugiura, Tomoko ; Okumura, Hidenori ; Umeda, Saki ; Nakamichi, Noritaka ; Watanabe, Yusuke ; Suzuki, Hiromichi ; Sunakawa, Yu ; Shimada, Ken ; Kawara, Kaori ; Sasaki, Yasutsuna ; Kato, Yukio
概要:
Purpose: Clinical study has previously revealed that plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38), an
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active metabolite of irinotecan, was higher in patients with end-stage renal failure than those with normal kidney function although SN-38 is mainly eliminated in the liver. Here, we focused on inhibition by uremic toxins of hepatic SN-38 uptake and down-regulation of uptake transporter(s) by uremic plasma in humans. Methods: We evaluated SN-38 uptake and its inhibition by uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), indoxyl sulfate (Indox), hippuric acid (HA) and indole acetate (IA), with cryopreserved human hepatocytes and HEK293 cells stably expressing hepatic uptake transporters, organic anion transporting polypeptides (OATPs). We also collected plasma samples from patients with severe renal failure to examine their effects on mRNA level of OATPs in primary cultured human hepatocytes. Results: SN-38 was taken up by hepatocytes, which showed biphasic saturation patterns. The SN-38 uptake by hepatocytes was significantly inhibited by a uremic toxin mixture including clinically relevant concentrations of CMPF, Indox, HA and IA. Kinetic analyses for OATP-mediated transport revealed that the uptake of SN-38 by OATP1B1 was the highest, followed by OATP1B3. Among the uremic toxins, CMPF exhibited most potent inhibition of OATP1B1-mediated SN-38 uptake and directly inhibited the uptake of SN-38 also in hepatocytes. In addition, gene expression of OATP1B1 and OATP1B3 in hepatocytes was significantly down-regulated by the treatment with the uremic plasma. Conclusions: OATP1B1-mediated hepatic uptake of SN-38 was inhibited by uremic toxins, and gene expression of OATP1B1 was down-regulated by uremic plasma. © 2013 Springer Science+Business Media New York.
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Nakamichi, Noritaka ; Taguchi, Takayuki ; Hosotani, Hiroshi ; Wakayama, Tomohiko ; Shimizu, Takuya ; Sugiura, Tomoko ; Iseki, Shoichi ; Kato, Yukio
概要:
The aim of the present study is to clarify the functional expression and physiological role in brain neurons of carnitin
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e/organic cation transporter OCTN1/SLC22A4, which accepts the naturally occurring antioxidant ergothioneine (ERGO) as a substrate in vivo. After intracerebroventricular administration, the distribution of [ 3H]ERGO in several brain regions of octn1 -/- mice was much lower than that in wild-type mice, whereas extracellular marker [ 14C]mannitol exhibited similar distribution in the two strains. The [ 3H]ERGO distribution in wild-type mice was well correlated with the amount of ERGO derived from food intake and the OCTN1 mRNA level in each brain region. Immunohistochemical analysis revealed colocalization of OCTN1 with neuronal cell markers microtubule-associated protein 2 (MAP2) and βIII-tubulin in mouse brain and primary cultured cortical neurons, respectively. Moreover, cultured cortical neurons exhibited time-dependent and saturable uptake of [ 3H]ERGO. These results demonstrate that OCTN1 is functionally expressed in brain neurons. The addition of ERGO simultaneously with serum to culture medium of cortical neurons attenuated mRNA and protein expressions of MAP2, βIII-tubulin and synapse formation marker synapsin I, and induced those of sex determining region Y-box 2 (Sox2), which is required to maintain the properties of undifferentiated neural stem cells. In neuronal model Neuro2a cells, knockdown of OCTN1 by siRNA reduced the uptake of [ 3H]ERGO with concomitant up-regulation of oxidative stress marker HO-1 and Sox2, and down-regulation of neurite outgrowth marker GAP43. Interestingly, the siRNA knockdown decreased the number of differentiated Neuro2a cells showing long neurites, but increased the total number of cells. Thus, OCTN1 is involved in cellular differentiation, but inhibits their proliferation, possibly via the regulation of cellular oxidative stress. This is the first evidence that OCTN1 plays a role in neuronal differentiation and proliferation, which are required for brain development. Crown Copyright © 2012.
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論文
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Shimizu, Takuya ; Kijima, Ai ; Masuo, Yusuke ; Ishimoto, Takahiro ; Sugiura, Tomoko ; Takahashi, Saki ; Nakamichi, Noritaka ; Kato, Yukio
概要:
5-Aminosalicylic acid (5-ASA) is an orally administered therapeutic agent for inflammatory bowel diseases, such as ulcer
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ative colitis and Crohn’s disease. We hypothesized that the absorption of 5-ASA is mediated by the polyspecific carnitine/organic cation transporter (OCTN1/SLC22A4), based on the similarity of chemical structure between 5-ASA and other OCTN1 substrates. Therefore, we examined the involvement of this transporter in the disposition of 5-ASA in vivo by using octn1 gene knockout (octn1−/−) mice. After oral administration of 5-ASA, the plasma concentrations of 5-ASA and its primary metabolite, N-acetyl-5-aminosalicylate (Ac-5-ASA), in octn1−/− mice were much lower than those in wild-type mice. The time required to reach maximum plasma concentration was also delayed in octn1−/− mice. On the other hand, the plasma concentration profiles of both 5-ASA and Ac-5-ASA after intravenous administration of 5-ASA (bolus or infusion) were similar in the two strains. Uptake of 5-ASA from the apical to the basal side of isolated small-intestinal tissues of octn1−/− mice, determined in an Ussing-type chamber, was lower than that in wild-type mice. Further, uptake of 5-ASA in HEK293 cells stably transfected with the OCTN1 gene, assessed as the sum of cell-associated 5-ASA and Ac-5-ASA, was higher than that in HEK293 cells transfected with the vector alone. Overall, these results indicate that OCTN1 is involved, at least in part, in the gastrointestinal absorption of 5-ASA.
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Masuo, Yusuke ; Nagamori, Shushi ; Hasegawa, Aoi ; Hayashi, Kazuki ; Isozumi, Noriyoshi ; Nakamichi, Noritaka ; Kanai, Yoshikatsu ; Kato, Yukio
概要:
Purpose: Monoamine oxidases (MAOs) are non-CYP enzymes that contribute to systemic elimination of therapeutic agents, an
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d localized on mitochondrial membranes. The aim of the present study was to validate quantitative estimation of metabolic clearance of MAO substrate drugs using human liver microsomes (HLMs). Methods: Three MAO substrate drugs, sumatriptan, rizatriptan and phenylephrine, as well as four CYP substrates were selected, and their disappearance during incubation with HLMs or mitochondria (HLMt) was measured. Metabolic clearance (CL) was then calculated from the disappearance curve. Results: CL obtained in HLMs for sumatriptan and a typical MAO substrate serotonin was correlated with that obtained in HLMt among ten human individual livers. Hepatic intrinsic clearance (CLint,vitro) estimated from CL in HLMs was 14–20 and 2–5 times lower than in vivo hepatic intrinsic clearance (CLint,vivo) obtained from literature for MAO and CYP substrates, respectively. Utilization of HLMs for quantitatively assessing metabolic clearance of MAO substrates was further validated by proteomics approach which has revealed that numerous proteins localized on inner and outer membranes of mitochondria were detected in both HLMs and HLMt. Conclusion: CLint,vitro values of MAO substrate drugs can be quantitatively estimated with HLMs and could be used for semi-quantitative prediction of CLint,vivo values. © 2017 Springer Science+Business Media New York<br />Embargo Period 12 months
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| 8.
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Hashimoto, Naoto ; Nakamichi, Noritaka ; Yamazaki, Erina ; Oikawa, Masashi ; Masuo, Yusuke ; Schinkel, Alfred H. ; Kato, Yukio
概要:
ATP binding cassette transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed in s
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kin, but their involvement in transdermal absorption of clinically used drugs remains unknown. Here, we examined their role in transdermal absorption of corticosteroids. Skin and plasma concentrations of dexamethasone after dermal application were reduced in P-gp and BCRP triple-knockout (Mdr1a/1b/Bcrp−/−) mice. The skin concentration in Mdr1a/1b/Bcrp−/− mice was reduced in the dermis, but not in the epidermis, indicating that functional expression of these transporters in skin is compartmentalized. Involvement of these transporters in dermal transport of dexamethasone was also supported by the observation of a higher epidermal concentration in Mdr1a/1b/Bcrp−/− than wild-type mice during intravenous infusion. Transdermal absorption after dermal application of prednisolone, but not methylprednisolone or ethinyl estradiol, was also lower in Mdr1a/1b/Bcrp−/− than in wild-type mice. Transport studies in epithelial cell lines transfected with P-gp or BCRP showed that dexamethasone and prednisolone are substrates of P-gp, but are minimally transported by BCRP. Thus, our findings suggest that P-gp is involved in transdermal absorption of at least some corticosteroids in vivo. P-gp might be available as a target for inhibition in order to deliver topically applied drugs and cosmetics in a manner that minimizes systemic exposure. © 2017 Elsevier B.V.<br />Embargo Period 12 months
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Shimizu, Takuya ; Kijima, Ai ; Masuo, Yusuke ; Ishimoto, Takahiro ; Sugiura, Tomoko ; Takahashi, Saki ; Nakamichi, Noritaka ; Kato, Yukio
概要:
5-Aminosalicylic acid (5-ASA) is an orally administered therapeutic agent for inflammatory bowel diseases, such as ulcer
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ative colitis and Crohn’s disease. We hypothesized that the absorption of 5-ASA is mediated by the polyspecific carnitine/organic cation transporter (OCTN1/SLC22A4), based on the similarity of chemical structure between 5-ASA and other OCTN1 substrates. Therefore, we examined the involvement of this transporter in the disposition of 5-ASA in vivo by using octn1 gene knockout (octn1−/−) mice. After oral administration of 5-ASA, the plasma concentrations of 5-ASA and its primary metabolite, N-acetyl-5-aminosalicylate (Ac-5-ASA), in octn1−/− mice were much lower than those in wild-type mice. The time required to reach maximum plasma concentration was also delayed in octn1−/− mice. On the other hand, the plasma concentration profiles of both 5-ASA and Ac-5-ASA after intravenous administration of 5-ASA (bolus or infusion) were similar in the two strains. Uptake of 5-ASA from the apical to the basal side of isolated small-intestinal tissues of octn1−/− mice, determined in an Ussing-type chamber, was lower than that in wild-type mice. Further, uptake of 5-ASA in HEK293 cells stably transfected with the OCTN1 gene, assessed as the sum of cell-associated 5-ASA and Ac-5-ASA, was higher than that in HEK293 cells transfected with the vector alone. Overall, these results indicate that OCTN1 is involved, at least in part, in the gastrointestinal absorption of 5-ASA.
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Tang, Yaliang ; Masuo, Yusuke ; Sakai, Yoshio ; Wakayama, Tomohiko ; Sugiura, Tomoko ; Harada, Ryuichi ; Futatsugi, Azusa ; Komura, Takuya ; Nakamichi, Noritaka ; Sekiguchi, Hirotaka ; Sutoh, Keita ; Usumi, Koji ; Iseki, Shoichi ; Kaneko, Shuichi ; Kato, Yukio
概要:
Xenobiotic transporters play key roles in disposition of certain therapeutic agents, although limited information is ava
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ilable on their roles other than pharmacokinetic issues. Here, suppressive effect of multispecific organic cation transporter OCTN1/SLC22A4 on liver fibrosis was proposed in liver injury models. After injection of hepatotoxins such as dimethylnitrosamine (DMN) or concanavalin A, hepatic fibrosis, and oxidative stress, evaluated in terms of Sirius red and 4-hydroxy-2-nonenal staining, respectively, were more severe in liver of octn1/slc22a4 gene knockout (octn1-/-) mice than that in wild-type mice. DMN treatment markedly increased α-smooth muscle actin and F4/80, markers of activated stellate and Kupffer cells, respectively, in liver of octn1-/-, but had less effect in wild-type mice. Thus, octn1/slc22a4 gene deletion results in more severe hepatic fibrosis, oxidative stress, and inflammation. DMN-treated wild-type mice showed increased Octn1 staining and hepatic concentration of its food-derived antioxidant ergothioneine (ERGO). The upregulated Octn1 was co-localized with α-smooth muscle actin. Functional expression of Octn1 was demonstrated in activated human hepatic stellate cell lines, LI90 and LX-2. Provision of ERGO-rich feed ameliorated DMN-induced liver fibrosis and oxidative stress. Overall, Octn1 is upregulated in activated stellate cells, resulting in increased delivery of its substrate antioxidant ERGO and a protective effect against liver fibrosis. © 2016 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.<br />Embargo Period 12 months
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