Details of a Researcher - ITAGAKI Shiro

Papers - ITAGAKI Shiro

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THE USEFULNESS OF ANTICANCER DRUG SENSITIVITY TEST (HDRA) FOR THE ADJUVANT CHEMOTHERAPY AND PROFILING IN PANCREATIC CANCER TISSUE AFTER HDRA

照井一史, 川崎仁司, 細井一広, 中川潤一, 板垣史郎, 津山博匡, 下山律子, 袴田健一, 早狩誠

The Hirosaki medical journal ( Hirosaki University ) 65 ( 2 ) 173 - 181 2014.09 [Refereed]

約10種の腫瘍組織（10種）についてHDRA 法による抗がん剤の感受性試験を行った．その結果，5-FU はすべての腫瘍組織に対し陽性を示し，CDDP も5-FU と同様に多くの腫瘍組織で陽性を示したが，抑制率はやや低下していた．術前に5-FU が投与されていない食道癌群における感受性の抑制率は71.9±11.6%（n = 6）であり，術前に5-FU が投与された食道癌群の抑制率に有意な差は認められず，測定した症例では耐性が生じていない可能性が示唆された．その後S-1 投与患者において，5-FU に感受性を示した群は，陰性群に比べ生存日数の延長が認められた.膵癌組織での5-FU およびGEM に対する感受性結果から，5-FU またはS-1 が膵癌への薬物療法で有用な薬剤である可能性が示唆された．膵癌組織に対する質量分析によるプロファイリングを行った結果，5-FU に対する感受性が陰性の試料に出現が増加するシグナルが，5-FU 無効例のバイオマーカーになる可能性が示唆された．

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ラット肝化学発癌過程におけるCyclophilin Bの発現変化

細井一広, 照井一史, 中川潤一, 下山律子, 津山博匡, 板垣史郎, 土田成紀, 早狩誠

弘前医学 164 - 172 2014.09 [Refereed]

PROFILING OF RAT BRAIN PEPTIDES TREATED WITH CENTRALLY ACTIVE ACE INHIBITOR

金澤佐知子, 細井一広, 照井一史, 下山律子, 中川潤一, 板垣史郎, 早狩誠

The Hirosaki medical journal ( Hirosaki University ) 65 ( 1 ) 95 - 103 2014.03 [Refereed]

本研究は，中枢移行性ACE 阻害剤（ACEI）による記憶保持亢進の機序を解明することである．中枢移行性ACEI（captopril），非中枢移行性ACEI （imidapril）およびARB（losartan）投与ラットでの脳内ペプチドの発現変化をHPLC 法およびTOF-MS 法を用いて検索した．その結果，TOF-MS 法では，captopril 投与群で特異的に発現が亢進するペプチドを多数検出できたが，その多くは質量数3,000以下であった．なお，これらの質量数はすべて一価イオンとして検出されたことから，すべて物質固有の質量数を反映していた．検出した質量数は，ACE が分解する脳内ペプチド（LH-RH,substance P, β-neoendorphin, neuromedin B, LVV-hemorphin-7, amyloid β-protein）やinsulin-regulated aminopeptidase（IRAP）の基質と考えられているvasopressin とは異なる値を示した．脳内にはACE やIRAP 以外にも活性中心にZn2+を有するメタロプロテアーゼが存在することから，今回得られた多くの質量数は，キレート形成能を有するcaptoprilにより阻害されたメタロプロテアーゼの内在性基質の可能性がある．

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Rapid Stimulating Effect of the Antiarrhythmic Agent Amiodarone on Absorption of Organic Anion Compounds

Masahiro Segawa, Jiro Ogura, Satoru Seki, Shirou Itagaki, Natsuko Takahashi, Masaki Kobayashi, Takeshi Hirano, Hiroaki Yamaguchi, Ken Iseki

DRUG METABOLISM AND PHARMACOKINETICS ( JAPANESE SOC STUDY XENOBIOTICS ) 28 ( 3 ) 178 - 186 2013.06 [Refereed]

In a clinical setting, changes in pharmacokinetics due to drug-drug interactions can often directly affect the therapeutic safety and efficacy of drugs. Recently, interest has been shown in drug-drug interactions in the intestine. It is now recognized that changes in the functions of drug transporters substantially influence the absorption of administered drugs from the intestine. Amiodarone (AMD) is a potent drug used in the treatment of serious supraventricular and ventricular tachyarrhythmias. Despite its potent pharmacological effects, its wide clinical use is precluded by drug-drug interactions. In this study, we characterized the transporter function between AMD and various compounds in human intestinal model Caco-2 cells. AMD significantly and rapidly increased the uptake of [H-3]estrone-3-sulfate (E-3-S) for 5 min. The apical-to-basal transport of [H-3]E-3-S was significantly increased by AMD. The AMD-stimulated [H-3]E-3-S uptake was inhibited by organic anion transporting polypeptide (OATP) substrates. Caco-2 cells treated with AMD showed increased OATP2B1 expression on the cell surface. AMD also increased the absorption of sulfobromophthalein (ESP), which is a typical organic anion compound, and the expression level of Oatp2b1 at the membrane in in vivo experiments. The results indicate that AMD induces OATP2B1/Oatp2b1 expression at the membrane in the intestine and enhances absorption of organic anion compounds.

DOI PubMed

アンジオテンシン変換酵素に焦点を当てた認知症患者への食事支援に関する基礎研究

内山道子, 板垣史郎, 金澤佐知子, 細井一広, 照井一史, 下山律子, 早狩誠

弘前医学 64 41 - 49 2013.05 [Refereed]

IDENTIFICATION OF THE ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN THE LOCAL PRODUCT OF AOMORI PREFECTURE

板垣史郎, 内山道子, 金澤佐知子, 細井一広, 照井一史, 下山律子

The Hirosaki medical journal ( Hirosaki University ) 64 ( 1 ) 50 - 57 2013.05 [Refereed]

本研究では，食事が多様な食品機能成分の摂取経路という一面を有し，疾病予防法を構築する上で有用な切り口であることを鑑み，アンジオテンシンＩから強力な血圧上昇を有するアンジオテンシンIIへの変換を司るアンジオテンシン変換酵素（ACE）を標的として，青森県特産の農産物及び水産物に含まれるACE阻害物質の探索を行った．青森県特産食材より蒸留水で抽出した抽出液について，ACE阻害活性の評価を行った．ACE阻害活性を示した抽出液から各種カラム分画法にてACE阻害活性物質を単離・精製し，質量分析法により，ACE阻害成分を同定した．その結果，カボチャ，ニンニク，大豆，大鰐モヤシの抽出液に特に強いACE阻害活性を見出した．その中から，カボチャを対象としてACE阻害活性成分の特定を試み，分子量303のムギネ酸前駆物質，ニコチアナミンがその機能実体である可能性を強く示唆する結果を得た．

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STUDY ON IMPROVEMENT OF THE ACCURACY AND PRECISION OF PREDICTED PLASMA CONCENTRATION OF VANCOMYCIN IN THE ADMINISTRATION PLANNING SUPPORT FOR CHILDREN

板垣史郎, 工藤正純, 新岡丈典, 内山道子, 金澤佐知子, 細井一広, 照井一史, 小島佳也, 保嶋実, 早狩誠

The Hirosaki medical journal ( Hirosaki University ) 64 ( 1 ) 58 - 64 2013.05 [Refereed]

小児バンコマイシン（VCM）投与設計支援時に散見される，血中濃度予測値と実測値のずれの原因を特定し，予測系の正確度精度向上を図った．VCM投与時にTDMが実施された16歳以下の患者のうち，クレアチニンクリアランス（CLcr）値が推定可能であった25名を解析対象とした．初回VCM血中濃度ならびにVCMクリアランスを成人母集団パラメータ（A-PPK）および小児母集団パラメータ（P-PPK）を用いて予測し，実測値との差（残差）を基に予測系の正確度精度を評価した．また，初回VCM血中濃度について残差と患者背景因子との相関性を評価した．初回VCM血中濃度，VCMクリアランス共にA-PPK使用系の正確度精度が良好であった．A-PPK使用系の初回VCM血中濃度は年齢，体重，体表面積と有意に相関しており，年齢に関するカットオフ値は6歳と推定された．小児においてCLcrが推定できる場合は，6歳以上を目安にCLcrが組み込まれているA-PPKを用いることが推奨される．

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処方せんチェックシートを用いたlevofloxacinの用法・用量チェックシステムの効果

岡村祐嗣, 高橋志織, 小原信一, 板垣史郎, 早狩誠

医薬品相互作用研究 36 1 - 6 2013.05 [Refereed]

Electrophysiological Characterization of the Polyspecific Organic Cation Transporter Plasma Membrane Monoamine Transporter

Shiro Itagaki, Vadivel Ganapathy, Horace T. B. Ho, Mingyan Zhou, Ellappan Babu, Joanne Wang

DRUG METABOLISM AND DISPOSITION ( AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS ) 40 ( 6 ) 1138 - 1143 2012.06 [Refereed]

Plasma membrane monoamine transporter (PMAT) is a polyspecific organic cation (OC) transporter that transports a variety of endogenous biogenic amines and xenobiotic cations. Previous radiotracer uptake studies showed that PMAT-mediated OC transport is sensitive to changes in membrane potential and extracellular pH, but the precise role of membrane potential and protons on PMAT-mediated OC transport is unknown. Here, we characterized the electrophysiological properties of PMAT in Xenopus laevis oocytes using a two-microelectrode voltage-clamp approach. PMAT-mediated histamine uptake is associated with inward currents under voltage-clamp conditions, and the currents increased in magnitude as the holding membrane potential became more negative. A similar effect was also observed for another cation, nicotine. Substrate-induced currents were largely independent of Na+ but showed strong dependence on membrane potential and pH of the perfusate. Detailed kinetic analysis of histamine uptake revealed that the energizing effect of membrane potentials on PMAT transport is mainly due to an augmentation of I-max with little effect on K-0.5. At most holding membrane potentials, I-max at pH 6.0 is approximately 3- to 4-fold higher than that at pH 7.5, whereas K-0.5 is not dependent on pH. Together, these data unequivocally demonstrate PMAT as an electrogenic transporter and establish the physiological inside-negative membrane potential as a driving force for PMAT-mediated OC transport. The important role of membrane potential and pH in modulating the transport activity of PMAT toward OCs suggests that the in vivo activity of PMAT could be regulated by pathophysiological processes that alter physiological pH or membrane potential.

DOI PubMed

効果発現パターンにより抗がん薬を分類するための基礎的検討

高橋夏子, 小林正紀, 板垣史郎, 平野剛, 武隈洋, 菅原満, 井関健

薬学雑誌 ( (公社)日本薬学会 ) 132 ( 6 ) 777 - 783 2012.06 [Refereed]

ヒト肺癌由来株化細胞A549およびヒト乳癌由来株化細胞MCF-7を用い、作用発現が明確な4種の薬物(シスプラチン(CDDP)、カルボプラチン(CBDCA)、パクリタキセル(PTX)、ゲムシタビン(GEM))を使用し、より簡便な抗癌薬の効果の判定と、投与設計への寄与を目的とし、in vitroでの抗癌薬の分類について基礎的検討を行った。CDDP、CBDCAは濃度依存的に抗腫瘍効果を発現する薬物として分類されることが推測された。一方、PTX、GEMについては細胞生存曲線の低濃度側へのシフトおよびIC 50値の著しい低下がみられことから、時間依存的に抗腫瘍効果を発揮する薬物として、分類可能であることが示唆された。更にCDDP、CBDCAの濃度依存性をより確実なものとするため、IC 50値を基準として前後10倍の濃度を設定し、濃度依存性を評価した結果、薬物濃度に比例した細胞生存率の低下がみられたことから、CDDP、CBDCAは濃度依存的に抗腫瘍効果を発揮する傾向の強い薬物であることが判明した。また、納所依存性の検討においても、用いた2種の細胞間で各抗癌薬の効果発現の様式に同様な傾向がみられた。研究結果より、細胞生存曲線及びIC 50値の変化を指標とし、作用の異なる抗癌薬を濃度依存的薬物および時間依存的薬物に分類できる可能性が示唆された。

Regulation of human monocarboxylate transporter 4 in skeletal muscle cells: The role of protein kinase C (PKC)

Katsuya Narumi, Masaki Kobayashi, Sho Otake, Ayako Furugen, Natsuko Takahashi, Jiro Ogura, Shirou Itagaki, Takeshi Hirano, Hiroaki Yamaguchi, Ken Iseki

INTERNATIONAL JOURNAL OF PHARMACEUTICS ( ELSEVIER SCIENCE BV ) 428 ( 1-2 ) 25 - 32 2012.05 [Refereed]

In the present study, to clarify the role of protein kinase C (PKC) in the regulation of monocarboxylate transporter 4 (MCT4) expression, we examined the regulation mechanism of MCT4 expression in human rhabdomyosarcoma (RD) cells, an in vitro skeletal muscle model. Exposure of RD cells to PMA, a PKC activator, for 24 h resulted in a two-fold increase in the amount of lactic acid in the growth medium. In parallel to an increase in lactic acid release from RD cells, the level of MCT4 mRNA and protein were also significantly increased in RD cells. A PKC inhibitory study indicated that PMA-induced stimulation of MCT4 expression can be mediated through a novel PKC isoform, especially PKC delta. Moreover, rottlerin, a selective PKC delta inhibitor, decreased PMA-induced MCT4 promoter activity. Deletion and mutational analysis suggested that the potential hypoxia-response elements (HREs) played a major role in the observed modulation of MCT4 expression by PMA. Furthermore, we found that small interfering RNA (siRNA)-mediated knockdown of hypoxia-inducible factor 1 alpha (HIF-1 alpha) significantly inhibited PMA-induced MCT4 promoter activity. Our results show that the effects of PMA on MCT4 expression are mediated through an indirect pathway partially involving PKC delta and HIF-1 alpha transcription factor. (C) 2012 Published by Elsevier B.V.

DOI PubMed

Effects of Acidification and Alkalinization Agent on Statins-induced Muscle Toxicity

Masaki Kobayashi, Kazuhiro Hidaka, Ikumi Chisaki, Natsuko Takahashi, Jiro Ogura, Shirou Itagaki, Takeshi Hirano, Hiroaki Yamaguchi, Ken Iseki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN ( PHARMACEUTICAL SOC JAPAN ) 132 ( 5 ) 609 - 615 2012.05 [Refereed]

The aim of this study was to determine the effects of alpha-cyano-4-hydroxycinnamic acid (CHC), a lactate efflux inhibitor, and citrate, an alkaline reagent, on statin-induced muscle injury using a human prototypic embryonal rhabdomyosarcoma cell line (RD) as a model of in vitro skeletal muscle and on statin-induced muscle damage in an in vivo study. Statin-induced reduction of cell viability and apoptosis was measured by the 3-(4,5-dimethylthiazol-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay and caspase assay. In an in vivo study, plasma creatine phosphokinase (CPK) level was examined in cerivastatin-treated rats. CHC increased growth inhibition of RD cells induced by cerivastatin, a lipophilic statin, but not these induced by pravastatin, a hydrophilic statin. On the other hand, citrate suppressed cerivastatin-, simvastatin- and atorvastatin-induced reduction of cell viability and caspase activation in RD cells. Moreover, citrate prevented cerivastatin-induced increase in CPK concentration in a concentration-dependent manner. This is first study to evaluate CHC or citrate-induced exacerbation or improvement of statin-induced muscle damage.

DOI PubMed

Intestinal Ischemia-Reperfusion Increases Efflux for Uric Acid Via Paracellular Route in the Intestine, but Decreases that Via Transcellular Route Mediated by BCRP

Jiro Ogura, Kaori Kuwayama, Atsushi Takaya, Yusuke Terada, Takashi Tsujimoto, Takahiro Koizumi, Hajime Maruyama, Asuka Fujikawa, Natsuko Takahashi, Masaki Kobayashi, Shirou Itagaki, Takeshi Hirano, Hiroaki Yamaguchi, Ken Iseki

JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES ( CANADIAN SOC PHARMACEUTICAL SCIENCES ) 15 ( 2 ) 295 - 304 2012 [Refereed]

Purpose. Uric acid is thought to be one of the most important antioxidants in human biological fluids. Intestinal ischemia-reperfusion (I/R) is an important factor associated with high rates of morbidity and mortality. Reactive oxygen species (ROS) are responsible for intestinal I/R injury. The aim of this study was to clarify the efflux for uric acid from the intestine after intestinal I/R. Methods. We used intestinal ischemia-reperfusion (I/R) model rats. Serosal to mucosal flux for [C-14]-uric acid was assessed by using Ussing-type diffusion chambers. BCRP/Bcrp expression was assessed by Western blot analysis. Caco-2 cells were used for a model of the intestinal epithelium, and rotenone was used as a mitochondrial dysfunction inducer. Results. Serosal to mucosal flux for uric acid was increased after intestinal I/R, and that for mannitol was also increased. Ko143, which is a BCRP inhibitor, did not affect the uric acid transport. The decreasing uric acid transport mediated by Bcrp was caused by decrease in the level of Bcrp homodimer, bridged by an S-S bond. The suppression of Bcrp S-S bond formation was associated with mitochondrial dysfunction. Moreover, BCRP S-S bond formation activity was decreased by rotenone in Caco-2 cells. Conclusions. Serosal to mucosal flux for uric acid is significantly increased via the paracelluler route, but that via the transcellular route mediated by Bcrp is decreased after intestinal I/R. The decreasing uric acid flux mediated by Bcrp is caused by suppression of Bcrp S-S bond formation. This suppression of Bcrp S-S bond formation may be related to mitochondrial dysfunction.

PubMed

Involvement of Cholesterol Membrane Transporter Niemann-Pick C1-Like 1 in the Intestinal Absorption of Lutein

Yuki Sato, Risa Suzuki, Masaki Kobayashi, Shirou Itagaki, Takeshi Hirano, Toshihiro Noda, Satoshi Mizuno, Mitsuru Sugawara, Ken Iseki

JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES ( CANADIAN SOC PHARMACEUTICAL SCIENCES ) 15 ( 2 ) 256 - 264 2012 [Refereed]

PURPOSE. Lutein is a carotenoid mainly found in green leafy vegetables and is located in the macula lutea in the human eye. Since humans cannot synthesize lutein de novo, it must be digested as food. The physiological importance of an orally administered compound depends on its interaction with target tissues. It is therefore important to clarify the absorption mechanism in the intestine. Cholesterol membrane transporters Niemann-Pick C1 Like 1 (NPC1L1) and scavenger receptor class B type 1 (SR-B1) are involved in the intestinal absorption of highly lipophilic compounds including cholesterol. Ezetimibe, a selective inhibitor of intestinal NPC1L1, is the widespread lipid-lowering agent. It is important to investigate the possibility of food-drug interactions in order to prevent undesirable and harmful clinical consequences. The aim of this work was to determine whether NPC1L1, SR-B1 and other transporters are involved in absorption of lutein. METHODS. Caco-2 cells were used for accumulation and permeability study of lutein. Lutein concentration was determined by an HPLC system. The cDNA of transporters was isolated from total RNA of Caco-2 cells, and the expression of these transporters was confirmed by RT-PCR (reverse transcription - polymerase chain reaction). RESULTS. Ezetimibe inhibited up to 40% of lutein accumulation by Caco-2 cell monolayers. Block lipid transport 1 (BLT-1), a selective chemical inhibitor of SR-B1, also inhibited lutein accumulation by Caco-2 cells. On the other hand, ATP-depletion reagents (sodium fluoride and sodium azide or carbonyl cyanide m-chlorophenylhydrazone) did not influence the accumulation or permeation of lutein significantly. CONCLUSIONS. The results show that lutein absorption is, at least in part, mediated by influx transporters NPC1L1 and SR-B1 rather than mediated by efflux transporters such as ABC (ATP-binding cassette) transporters.

PubMed

The Decrease in Farnesoid X Receptor, Pregnane X Receptor and Constitutive Androstane Receptor in the Liver after Intestinal Ischemia-Reperfusion

Jiro Ogura, Yusuke Terada, Takashi Tsujimoto, Takahiro Koizumi, Kaori Kuwayama, Hajime Maruyama, Asuka Fujikawa, Atsushi Takaya, Masaki Kobayashi, Shirou Itagaki, Natsuko Takahashi, Takeshi Hirano, Hiroaki Yamaguchi, Ken Iseki

JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES ( CANADIAN SOC PHARMACEUTICAL SCIENCES ) 15 ( 5 ) 616 - 631 2012 [Refereed]

Purpose. Intestinal ischemia-reperfusion (I/R) damages remote organs, including the liver, and promotes multi-organ failure (MOF). However, the molecular mechanisms underlying acute liver injury after intestinal I/R have not been completely elucidated. Farnesoid X receptor (FXR), pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulate metabolizing enzymes and transporters, and coordinately prevent hepatotoxicity reflecting an inability of appropriate excretion of endogenous toxic compounds. In this study, we assessed FXR, PXR and CAR expression levels and their localization levels in nuclei in the liver after intestinal I/R. We also investigated the effect of IL-6 on FXR, PXR and CAR expression levels and their localization levels in nuclei in in vitro experiments. Methods. We used intestinal I/R model rats. Moreover, HepG2 cells were used in in vitro study. Real-time PCR and Western blotting were used to assess mRNA and protein expression levels. Nuclear receptor localization in nuclei was analyzed by Western blotting using nuclear extracts. Results. FXR and PXR expression levels began to be decreased at 3 h, and FXR, PXR and CAR expression levels were decreased at 6 h after intestinal I/R. The localization levels of FXR, PXR and CAR in nuclei began to be decreased at 3 h, and all of them were decreased at 6 h after intestinal I/R. In HepG2 cells, FXR, PXR and CAR expression levels were decreased by 0.5-1 ng/mL, 0.5-100 ng/mL and 100 ng/mL IL-6 treatment for 24 h, respectively. FXR, PXR and CAR localization levels in nuclei were suppressed by 0.5-10 ng/mL, 10-100 ng/mL and 10-100 ng/mL IL-6 treatment for 24 h, respectively. Conclusions. FXR, PXR and CAR expression levels are decreased in the liver after intestinal I/R. IL-6 is one of main causes the decreases in expressions of these receptors.

PubMed

Protective Effect of Soy Isoflavone Genistein on Ischemia-Reperfusion in the Rat Small Intestine

Yuki Sato, Shirou Itagaki, Setsu Oikawa, Jiro Ogura, Masaki Kobayashi, Takeshi Hirano, Mitsuru Sugawara, Ken Iseki

BIOLOGICAL & PHARMACEUTICAL BULLETIN ( PHARMACEUTICAL SOC JAPAN ) 34 ( 9 ) 1448 - 1454 2011.09 [Refereed]

Ischemia-reperfusion (I/R) injury of the intestine is an important factor associated with high rates of morbidity and mortality. Intestinal I/R is a common clinical problem in the settings of severe burns, circulatory shock and strangulation ileus. Intestinal I/R damages remote organs and promotes multi-organ failure. It has been shown that enteral feeding before ischemic insults is beneficial for reducing organ injury and improving survival after intestinal I/R. In that study, the authors used a standard complex enteral diet and they suggested that it is important to find new nutrient formulas. Since reactive oxygen species are responsible for intestinal I/R injury, we focused on a dietary polyphenol, the soy isoflavone genistein. Genistein has a wide spectrum of biochemical and pharmacological activities. However, the possibility of a protective effect of genistein as enteral nutrition on I/R injury has not been investigated. We therefore investigated the protective effect of genistein on oxidative injury using intestinal I/R model rats. We found that genistein, which has combined antioxidant activity from radical scavenging, xanthine oxidase inhibition and chain-breaking effects, exhibits a protective effect on intestinal I/R injury. The results suggest that genistein, a soy isoflavone, has the possibility as a new nutrient formula of enteral feeding.

DOI PubMed CiNii

Protective effect of lutein after ischemia-reperfusion in the small intestine

Yuki Sato, Masaki Kobayashi, Shirou Itagaki, Takeshi Hirano, Toshihiro Noda, Satoshi Mizuno, Mitsuru Sugawara, Ken Iseki

FOOD CHEMISTRY ( ELSEVIER SCI LTD ) 127 ( 3 ) 893 - 898 2011.08 [Refereed]

Lutein is a carotenoid mainly found in green leafy vegetables and is located in the macula lutea in the human eye. Since humans cannot synthesise lutein de novo, it must be digested as food. The physiological importance of an orally administered compound depends on its interaction with target tissues. There is little information about the effects of intake of lutein in tissues other than the eyes. The aim of this study was to clarify the protective effect of lutein against oxidative injury using ischemia-reperfusion (I/R) model rats and to determine the relationship between pharmacokinetics and antioxidant activity of lutein. Intestinal I/R was induced by 30-min occlusion of the superior mesenteric artery followed by 60-min reperfusion. After 60 min of reperfusion, intestinal tissue was Used for analysis of Evans blue dye extravasation, lipid peroxidation and myeloperoxidase activity. Lutein administered before I/R had a significant protective effect against oxidative injury. (C) 2011 Elsevier Ltd. All rights reserved.

DOI CiNii

Regulation mechanism of ABCA1 expression by statins in hepatocytes

Masaki Kobayashi, Keisuke Gouda, Ikumi Chisaki, Manami Ochiai, Shirou Itagaki, Ken Iseki

EUROPEAN JOURNAL OF PHARMACOLOGY ( ELSEVIER SCIENCE BV ) 662 ( 1-3 ) 9 - 14 2011.07 [Refereed]

ATP-binding cassette transporter A1 (ABCA1) is predicted to be involved in the control of apolipoprotein AI-mediated cholesterol efflux: biosynthesis of high-density lipoprotein (HDL). However, the effects of HMG-CoA reductase inhibitors (statins) on ABCA1 in the liver and the precise mechanisms of their actions have been obscure. The aims of this study were to determine whether statins (atorvastatin (Ato) and pitavastatin (Pit)) affect hepatic ABCA1 expression and to clarify the mechanisms of their actions using HepG2 cells and the rat liver. We examined alterations in mRNA and protein levels of ABCA1 and peroxisome proliferator-activated receptors (PPARs) by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. In vitro and in vivo studies suggested that Pit increases ABCA1 mRNA level, but not Ato. Pit greatly increased Abca1 mRNA level and also increased the amount of plasma HDL and the mRNA level of PPAR alpha. Clofibrate (PPAR alpha agonist) increased ABCA1 expression in HepG2 cells and rat primary hepatocytes more than did PPAR beta/delta and gamma agonists. Pit-induced ABCA1 expression alteration was blocked by GW6471 (PPAR alpha antagonist) and by PPAR alpha knockdown. In this study, we demonstrated that Pit affect ABCA1 expression via PPAR alpha in hepatocytes. The strategy to target a PPAR alpha agonist in the liver can lead to increases in ABCA1 expression and HDL level. (C) 2011 Elsevier B.V. All rights reserved.

DOI

Pharmacokinetic properties of lutein emulsion after oral administration to rats and effect of food intake on plasma concentration of lutein

Yuki Sato, Masaki Kobayashi, Shirou Itagaki, Takeshi Hirano, Toshihiro Noda, Satoshi Mizuno, Mitsuru Sugawara, Ken Iseki

BIOPHARMACEUTICS & DRUG DISPOSITION ( WILEY-BLACKWELL ) 32 ( 3 ) 151 - 158 2011.04 [Refereed]

Lutein is a carotenoid found mainly in green leafy vegetables and is located in the macula lutea in the human eye. An intake of lutein as food is needed since humans cannot synthesize it de novo. Although lutein has received much attention recently due to its antioxidant activities, little information about the pharmacokinetic properties of lutein is available. Lutein emulsion formulation was used and the pharmacokinetics of lutein emulsion after oral administration to rats was investigated. The bioavailability of lutein using this formulation was calculated to be 5.20%. It was found that a large amount of lutein was accumulated in the intestinal mucosa. The absorption of orally administered compounds in the intestine can be enhanced by interaction with food or food components. Thus, the effect of food intake on the intestinal absorption of lutein was investigated. The plasma concentration of lutein after oral administration of the emulsion formulation was improved significantly by food intake. It is possible that the absorption of lutein in the intestine is improved significantly by some food components. Bile acids may also play important roles in the intestinal absorption of lutein since the absorption of lipophilic compounds such as cholesterol is related to bile acids. The results of these studies should contribute to an improvement of lutein absorption and provide important information for obtaining more effective pharmacological effects of lutein. Copyright (C) 2011 John Wiley & Sons, Ltd.

DOI PubMed

Alteration of P-gp Expression after Intestinal Ischemia-reperfusion Following 16-h Fasting in Rats

Jiro Ogura, Asuka Fujikawa, Hajime Maruyama, Masaki Kobayashi, Shirou Itagaki, Ken Iseki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN ( PHARMACEUTICAL SOC JAPAN ) 131 ( 3 ) 453 - 462 2011.03 [Refereed]

Alteration of P-glycoprotein (P-gp) expression influences the pharmacokinetics of P-gp substrates after intestinal ischemia-reperfusion (I/R). Fasting before intestinal I/R affects intestinal I/R injury. However, the effect of fasting on the alteration of P-gp expression after intestinal I/R has not been clarified. We previously reported that P-gp expression was altered after intestinal I/R following feeding. In the present study, we investigated the expression of P-gp after intestinal I/R following 16-h fasting. The mdr1a levels were decreased at 6 h in the jejunum, at I h in the ileum, at 6 and 24 h in the liver and at 6 h in the kidney. The mdr1b levels were decreased at 6 h in the ileum and at 1 and 6 h in the kidney. The mdr1b level in the liver was increased at 1 and 6 h. The expression of P-gp was decreased at 6 h in the jejunum, at 1, 6 and 24 h in the ileum, and at 6 h in the kidney. These alterations were different to those after intestinal I/R following feeding. In particular, the decrease in P-gp expression in the 16-h fasting I/R rats occurred at an early time during reperfusion compared with that in the feeding I/R rats. In conclusion, feeding condition affects the alteration of P-gp expression after intestinal I/R. Therefore, it is important to understand the patient's feeding condition for safe drug therapy.

DOI CiNii

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