{"created":"2023-07-27T06:44:30.715047+00:00","id":34762,"links":{},"metadata":{"_buckets":{"deposit":"9b8b64e4-e0ab-4bda-8b7e-03f72fa834f8"},"_deposit":{"created_by":3,"id":"34762","owners":[3],"pid":{"revision_id":0,"type":"depid","value":"34762"},"status":"published"},"_oai":{"id":"oai:kanazawa-u.repo.nii.ac.jp:00034762","sets":["2812:2813:2828"]},"author_link":["97518","29"],"item_9_biblio_info_8":{"attribute_name":"書誌情報","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2006-05-01","bibliographicIssueDateType":"Issued"},"bibliographicPageStart":"6p.","bibliographicVolumeNumber":"2004-2005","bibliographic_titles":[{"bibliographic_title":"平成17(2005)年度科学研究費補助金 基盤研究(C) 研究報告書"},{"bibliographic_title":"2005 Fiscal Year Final Research Report","bibliographic_titleLang":"en"}]}]},"item_9_creator_33":{"attribute_name":"著者別表示","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{}],"nameIdentifiers":[{},{}]}]},"item_9_description_21":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"本研究はトランスポーターによる薬物の生体膜透過に焦点を当て、排泄過程における薬物間相互作用を試験管レベルから定量的に予測するための分子的基盤の構築を目的とした。モデル薬物として、肝排泄型である新規尿酸生合成阻害薬Y-700のヒトおよびラット肝細胞への取り込み機構を解析したところ、Y-700が既知のトランスポーターfamilyであるOATPとは異なる有機アニオン輸送機構によってNa依存的に取り込まれること、その分子機構の一つは胆汁酸トランスポーターNTCPであることを明らかとした。また腎排泄型のモデル薬物として新規ループ利尿薬M17055の腎皮質切片への取込み機構を解析したところ、有機アニオントランスポーターOAT1が少なくとも一部、関与することが示唆された。さらに、腎刷子縁膜トランスポーターであるPEPT2、OCTN1、OCTN2とPDZドメインを有する細胞内タンパク質(PDZK1およびPDZK2)との特異的な相互作用を見出し、PDZK1およびPDZK2が、これらトランスポーターの輸送機能や細胞内局在の制御機構として働くことを見出した。また、細胞内外のH^+勾配を利用してβラクタム系抗生物質等を輸送するペプチドトランスポーターPEPT1と、細胞内外のNa^+勾配を利用してH^+濃度勾配を供給するNa^+/H^+ exchanger(NHE)3に着目し、NHE3共存下においてPEPT1の輸送活性ならびに輸送のpHおよびNa依存性が変化することを明らかとした。以上本研究により、トランスポーター分子群のみならず、トランスポーターと直接結合しうるPDZK1等のアダプタータンパク質、さらにはアダプター分子を介してトランスポーターと相互作用しうるNHE3等の膜タンパク質など、これまで相互作用への関与が知られていなかった多くのタンパク質の、分子基盤としての重要性を提示することができた。","subitem_description_type":"Abstract"},{"subitem_description":"Recent progress in molecular biology has revealed predominant roles of many types of xenobiotic transporters in drug secretion into the urine and bile, leading to possible occurrence of drug-drug interaction at the excretion processes. Therefore, it is expected to predict the interaction based on in vitro experimental system. This study aimed to clarify molecular basis for the prediction of drug-drug interaction at the excretion process in liver and kidney. As model drugs that are excreted into the bile and urine, a novel uric acid generation inhibitor Y-700 and a novel diuretic M17055 were used. We have suggested involvement of Na^+-dependent organic anion transport system, other than OATP family, in hepatic uptake of Y-700, part of Y-700 uptake being mediated by bile acid transporter NTCP. We have also clarified important role of OAT1 in renal uptake of M17055. Furthermore, we have identified direct interaction of certain types of transporters, that are expressed on apical membranes in kidney and/or small intestine, with PDZ domain containing proteins PDZK family, implying that such protein-protein interaction may play a role in apical localization of the transporters. Among the PDZ proteins, PDZK1 is colocalized on apical membranes in kidney and small intestine with OCTN2, and can stimulate transport activity of several transporters including OCTN1, OCTN2 and PEPT2. Finally, we have focused on functional modulation of oligopeptide transporter PEPT1 by Na^+/H^+ exchanger (NHE) 3 that can also bind to the PDZ proteins and supply H^+ gradient that can be utilized by PEPT1 for transport activity. NHE3 affects transport activity, Na^+- and H^+- dependence of PEPT1. Thus, this study has proposed a novel concept that adaptor proteins (such as PDZK1) and other membrane proteins (such as NHE3), both having interaction potential with transporters, could be important molecular basis for prediction of drug-drug interaction at excretion processes.","subitem_description_type":"Abstract"}]},"item_9_description_22":{"attribute_name":"内容記述","attribute_value_mlt":[{"subitem_description":"研究課題/領域番号:16590108, 研究期間(年度):2004–2005","subitem_description_type":"Other"},{"subitem_description":"出典：「肝腎トランスポーターを介した薬物間相互作用の分子基盤」研究成果報告書　課題番号16590108\n  (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)\n　　　本文データは著者版報告書より作成","subitem_description_type":"Other"}]},"item_9_identifier_registration":{"attribute_name":"ID登録","attribute_value_mlt":[{"subitem_identifier_reg_text":"10.24517/00034749","subitem_identifier_reg_type":"JaLC"}]},"item_9_relation_28":{"attribute_name":"関連URI","attribute_value_mlt":[{"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://kaken.nii.ac.jp/search/?qm=30251440","subitem_relation_type_select":"URI"}},{"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16590108/","subitem_relation_type_select":"URI"}},{"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-16590108/165901082005kenkyu_seika_hokoku_gaiyo/","subitem_relation_type_select":"URI"}}]},"item_9_version_type_25":{"attribute_name":"著者版フラグ","attribute_value_mlt":[{"subitem_version_resource":"http://purl.org/coar/version/c_ab4af688f83e57aa","subitem_version_type":"AM"}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2017-10-05"}],"displaytype":"detail","filename":"PH-PR-KATO-Y-kaken-2006-6p.pdf","filesize":[{"value":"319.6 kB"}],"format":"application/pdf","licensetype":"license_note","mimetype":"application/pdf","url":{"label":"PH-PR-KATO-Y-kaken-2006-6p.pdf","url":"https://kanazawa-u.repo.nii.ac.jp/record/34762/files/PH-PR-KATO-Y-kaken-2006-6p.pdf"},"version_id":"49613255-1cb4-4cad-b73d-e6acf9355cc5"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"jpn"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"research report","resourceuri":"http://purl.org/coar/resource_type/c_18ws"}]},"item_title":"肝腎トランスポーターを介した薬物間相互作用の分子基盤","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"肝腎トランスポーターを介した薬物間相互作用の分子基盤"},{"subitem_title":"Molecular basis for quantitative prediction of drug-drug interaction at excretion process","subitem_title_language":"en"}]},"item_type_id":"9","owner":"3","path":["2828"],"pubdate":{"attribute_name":"公開日","attribute_value":"2017-10-05"},"publish_date":"2017-10-05","publish_status":"0","recid":"34762","relation_version_is_last":true,"title":["肝腎トランスポーターを介した薬物間相互作用の分子基盤"],"weko_creator_id":"3","weko_shared_id":3},"updated":"2023-07-27T14:32:11.239972+00:00"}