{"created":"2023-07-27T06:44:28.909762+00:00","id":34721,"links":{},"metadata":{"_buckets":{"deposit":"9adc9949-b3a6-4c90-b0ff-650680a4c8be"},"_deposit":{"created_by":3,"id":"34721","owners":[3],"pid":{"revision_id":0,"type":"depid","value":"34721"},"status":"published"},"_oai":{"id":"oai:kanazawa-u.repo.nii.ac.jp:00034721","sets":["2812:2813:2826"]},"author_link":["97518","29"],"item_9_biblio_info_8":{"attribute_name":"書誌情報","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2008-05-01","bibliographicIssueDateType":"Issued"},"bibliographicPageStart":"8p.","bibliographicVolumeNumber":"2006-2007","bibliographic_titles":[{"bibliographic_title":"平成19(2007)年度 科学研究費補助金 基盤研究(C) 研究成果報告書"},{"bibliographic_title":"2007 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":"細胞膜裏打ちタンパク質PDZKは、これまでの加藤らの検討から、多くの薬物トランスポーターと相互作用することがin vitroで示されているが、その薬物動態制御因子としての役割は全く不明であった。本研究では、2年間に渡る研究成果を基に次の結論を得るに至った。 1.PDZK1は薬物を輸送するトランスポーターであるPEPT1、PEPT2(いずれもペプチドトランスポーター)、OCTN1、OCTN2(いずれも有機カチオン/カルニチントランスポーター)の薬物輸送能に影響を与える制御因子であること。一方で、PDZK2は少なくともOCTN2の制御因子であること。 2.PDZK1はPET1、OCTN2、有機アニオントランスポーターOATP1Aと、小陽吸収上皮細胞または腎近位尿細管刷子縁膜表面において共局在する一方、PDZK2は近位尿細管刷子縁膜直下でOCTN2と共局在すること。 3.PDZK1が小腸の細胞膜表面におけるPEPT1、OCTN2、OATP1Aの局在に必須の因子であり、PDZK1の欠損によってこれらトランスポーターの機能および局在不全が起こること。 4.低分子量GTP結合タンパク質Rab8が、PEPT1およびグルコーストランスポーターSGLT1の小腸細胞膜表面での局在に必須であり、その遺伝子欠損は栄養吸収不全を引き起こすこと。 以上の知見は薬物を輸送するトランスポーターやひいてはトランスポーターによる薬物動態の制御因子としてのアダプター分子(PDZK1、Rab8)の役割をin vivoおよびin vitroで実証した初めての例であり、複数のトランスポーターが複数のアダプターを介したネットワークとして機能することを示し、今後の医薬品開発や臨床における適正使用において薬物動態を考える上での重要な知見である。","subitem_description_type":"Abstract"},{"subitem_description":"Many types of xenobiotic transporters have been identified. They generally exhibit multispecific recognition of various types of substrates, and mediate membrane permeation of therapeutic agents, thereby playing important roles in drug absorption and disposition. We have recently proposed that protein-protein interactions involving the xenobiotic transporters may affect their function, localization and expression on plasma membranes based on in vitro experimental data. So-called adaptor proteins that directly interact with the transporters include PDZ (PSD95, Dig and ZOO domain-containing proteins. This project was performed with an aim to clarify pharmacokinetic roles of such adaptor proteins in vivo. Using pdzk1 gene knockout (pdzk1^+) mice, it was found that interaction with a PDZ adaptor PDZK1 is essential for the cell-surface localization of three solute carriers, Slc15a1 (oligopeptide transporter PEPTD, S1c22a5 (carnitine/organic cation transporter OCTN2) and Slco 1a (organic ani on transporting polypeptide, OATP1A) in mouse small intestine. Electron microscopy revealed localization of PEPT1 in intracellular vesicular structures in pdzk1^+ mice. In pdzk1^+ mice, gastrointestinal absorption of cephalexin, a substrate of PEPT1 and carnitine, a substrate of OCTN2 was delayed, compared with wild mice. In addition, uptake of estrone sulfate, a substrate of OATP1A from apical membrane of small intestine was also decreased in pdzk1^+ mice. Thus, PDZK1 plays pivotal roles as a regulator of transporters, thereby affecting the absorption of substrates of those interacting transporters. Since PDZ adaptors have multiple PDZ domains in their structure, and each PDZ domain can interact with the cytosolic region of the transporters, it can be speculated that transporters are localized within networks consisting of several transporters and adaptors. We have also found that apical localization of PEPT1 and Slc5a1 (sodium/glucose cotransporter, SGLT1) was almost completely reduced in gene knockout mice for small GTP-binding protein rab8 (rab8^+). Gastrointestinal uptake across the apical membranes of glycylsarcosine, a substrate of PEPT1 and α-methylglucose, a substrate of SGLT1 was concomitantly reduced in rab8^+. Thus, our results demonstrate that rab8 is necessary for the proper localization of the two transporters and digestion of various nutrients which are the substrate of those transporters.","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:18590137, 研究期間(年度):2006–2007","subitem_description_type":"Other"},{"subitem_description":"出典：「薬物動態制御因子としてのトランスポーターアダプターの役割」研究成果報告書　課題番号18590137\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":"10.24517/00034708","subitem_identifier_reg_type":"JaLC"}]},"item_9_publisher_17":{"attribute_name":"公開者","attribute_value_mlt":[{"subitem_publisher":"金沢大学自然科学研究科"}]},"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-18590137/","subitem_relation_type_select":"URI"}},{"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-18590137/185901372007kenkyu_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-2008-8p.pdf","filesize":[{"value":"371.4 kB"}],"format":"application/pdf","licensetype":"license_11","mimetype":"application/pdf","url":{"label":"PH-PR-KATO-Y-kaken-2008-8p.pdf","url":"https://kanazawa-u.repo.nii.ac.jp/record/34721/files/PH-PR-KATO-Y-kaken-2008-8p.pdf"},"version_id":"0733bdea-9c65-4e9d-b0d4-ea348db73224"}]},"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":"薬物動態制御因子としてのトランスポーターアダプターの役割","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"薬物動態制御因子としてのトランスポーターアダプターの役割"},{"subitem_title":"Roles of transporter adaptors as regulatory mechanism for drug absorption and disposition","subitem_title_language":"en"}]},"item_type_id":"9","owner":"3","path":["2826"],"pubdate":{"attribute_name":"公開日","attribute_value":"2017-10-05"},"publish_date":"2017-10-05","publish_status":"0","recid":"34721","relation_version_is_last":true,"title":["薬物動態制御因子としてのトランスポーターアダプターの役割"],"weko_creator_id":"3","weko_shared_id":3},"updated":"2023-07-27T14:25:00.358267+00:00"}