Molecular mechanisms of transcriptional regulation of the intestinal and renal drug transporters in the normal and disease states.

2009 Fiscal Year Final Research Report

• Project/Area Number: 19689013
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Applied pharmacology
• Research Institution: Kyoto University
• Principal Investigator: TERADA Tomohiro Kyoto University, 医学研究科, 副薬剤部長 (10324641)
• Project Period (FY): 2007 – 2009
• Keywords: 薬物トランスポータ / 転写制御 / 小腸 / 腎臓 / 生活習慣病

Research Abstract

We demonstrated the basal transcriptional mechanisms of three kinds of drug transporters such as renal organic anion transporter 1 (OAT1). It was found that renal OAT3 is up-regulated during cholestasis, and is responsible for renal secretion of bile acids. We identified a SNP in the promoter region that affecting the promoter activity of H^+/organic cation antiporter (MATE1). Mate1 knockout mice were newly developed, and we clarified the pharmacokinetic roles of MATE1 in vivo. Heterozygous MATE variants could not influence the disposition of metformin in diabetic patients by the clinical pharmacokinetic study. These information should be useful to consider the pathophysiological roles and to apply the personalized pharmacotherapy of drug transporters

Research Products

• [Journal Article] Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients. (2010)
  • Author(s): Toyama, K., Yonezawa, A., Tsuda, M., Masuda, S., Yano, I., Terada, T., Osawa, R., Katsura, T., Hosokawa, M., Fujimoto, S., Inagaki, N., Inui, K.
  • Journal Title: Pharmacogent.Gemonics 20(2) Pages: 135-138
  • Peer Reviewed
• [Journal Article] Human organic anion transporter hOAT4 is a transporter of perfluorooctanoic acid. (2009)
  • Author(s): Koizumi, A., Terada, T., Harada, K., Nakagawa, H., Inoue, K., Inui, K., Hitomi, T.
  • Journal Title: Basic Clin.Pharmacol.Toxicol. 105(2) Pages: 136-138
  • Peer Reviewed
• [Journal Article] Impact of regulatory polymorphisms in organic anion transporter genes in the human liver. (2009)
  • Author(s): Aoki, M., Terada, T., Ogasawara, K., Katsura, T., Hatano, E., Ikai, I., Inui, K.
  • Journal Title: Pharmacogenet Genomics 19(8) Pages: 647-656
  • Peer Reviewed
• [Journal Article] Targeted disruption of the multidrug and toxin extrusion 1 (Mate1) gene in mice reduces renal secretion of metformin. (2009)
  • Author(s): Tsuda, M., Terada, T., Mizuno, T., Katsura, T., Simakura, J.and Inui, K.
  • Journal Title: Mol.Pharmacol.(Accelerated Communication) 75(6) Pages: 1280-1286
  • Peer Reviewed
• [Journal Article] Involvement of human multidrug and toxin extrusion 1 (MATE1) in the drug interaction between cimetidine and metin renal epithelial cells. (2009)
  • Author(s): Tsuda, M., Terada, T., Ueba, M., Sato, T., Masuda, S., Katsura, T., Inui, K.
  • Journal Title: J.Pharmacol.Exp.Ther. 329(1) Pages: 185-191
  • Peer Reviewed
• [Journal Article] UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients. (2009)
  • Author(s): Onoue, M., Terada, T., Kobayashi, M., Katsura, T., Matsumoto, S., Yanagihara, K., Nishimura, T., Kanai, M., Teramukai, S., Shimizu, A., Fukushima, M., Inui, K.
  • Journal Title: Int.J.Clin.Oncol. 14(2) Pages: 136-142
  • Peer Reviewed
• [Journal Article] Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity. (2009)
  • Author(s): Kajiwara, M., Terada, T., Ogasawara, K., Iwano, J., Katsura, T., Fukatsu, A., Doi, T., Inui, K.
  • Journal Title: J.Hum.Genet. 54(1) Pages: 40-46
  • Peer Reviewed
• [Journal Article] Inhibitory effect of zinc on the absorption of b-lactam antibiotic ceftibuten via the peptide transporters in rats. (2008)
  • Author(s): Okamura, M., Terada, T., Katsura, T., Inui, K.
  • Journal Title: Drug Metab.Pharmacokinet. 23(6) Pages: 464-468
  • Peer Reviewed
• [Journal Article] Regulation of basal core promoter activity of human organic cation transporter 1 (OCT1/SLC22A1). (2008)
  • Author(s): Kajiwara, M., Terada, T., Asaka, J., Aoki, M., Katsura, T., Ikai, I., Inui, K.
  • Journal Title: Am.J.Physiol.Gastrointest.Liver Physiol. 295(6) Pages: G1211-G1216
  • Peer Reviewed
• [Journal Article] Significance of OCT3/SLC22A3, organic cation transporter 3, expression for the cytotoxic effect of oxaliplatin in colorectal cancer. (2008)
  • Author(s): Yokoo, S., Masuda, S., Yonezawa, A., Terada, T., Katsura, T.< Inui, K.
  • Journal Title: Drug Metab.Dispos. 36(11) Pages: 2299-2306
  • Peer Reviewed
• [Journal Article] Regulatory mechanism governing the diurnal rhythm of intestinal H^+/peptide cotransporter 1 (PEPT1). (2008)
  • Author(s): Saito, H., Terada, T., Shimakura, J., Katsura, T., Inui, K.
  • Journal Title: Am.J.Physiol.Gastrointest.Liver Physiol. 295(2) Pages: G395-G402
  • Peer Reviewed
• [Journal Article] Adaptive responses of renal organic anion transporter 3 (OAT3) during cholestasis. (2008)
  • Author(s): Chen, J., Terada, T., Ogasawara, K., Katsura, T., Inui, K.
  • Journal Title: Am.J.Physiol.Renal Physiol. 295(1) Pages: F247-F252
  • Peer Reviewed
• [Journal Article] Kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) is regulated by DNA methylation. (2008)
  • Author(s): Aoki, M., Terada, T., Kajiwara, M., Ogasawara, K., Ikai, I., Ogawa, O., Katsura, T., Inui, K.
  • Journal Title: Am.J.Physiol.Renal Physiol. 295(1) Pages: F165-F170
  • Peer Reviewed
• [Journal Article] Analyses of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney. (2008)
  • Author(s): Ogasawara, K., Terada, T., Motohashi, H., Asaka, J., Aoki, M., Katsura, T., Kamba, T., Ogawa, O., Inui, K.
  • Journal Title: J.Hum.Genet. 53(7) Pages: 607-614
  • Peer Reviewed
• [Journal Article] Altered pharmacokinetics of cationic drugs caused by down-regulation of renal rOCT2 (Slc22a2) and rMATE1 (Slc47a1) in ischemia/reperfusion-induced acute kidney injury. (2008)
  • Author(s): Matsuzaki, T., Morisaki, T., Sugimoto, W., Yokoo, K., Sato, D., Nonoguchi, H., Tomita, K., Terada, T., Inui, K., Hamada, A., Saito, H.
  • Journal Title: Drug Metab.Dispos. 36(4) Pages: 649-654
  • Peer Reviewed
• [Journal Article] Roles of organic anion transporters in the renal excretion of perfluorooctanoic acid. (2008)
  • Author(s): Nakagawa, H., Hirata, T., Terada, T., Jutabha, P., Miura, D., Harada, K., Inoue, K., Anzai, N., Endou, H., Inui, K., Kanai, Y., Koizumi, A.
  • Journal Title: Basic Clin.Pharmacol.Toxicol. 103(1) Pages: 1-8
  • Peer Reviewed
• [Journal Article] Physiological and pharmacokinetic roles of H^+/organic cation antiporters (MATE/SLC47A).Biochem. (2008)
  • Author(s): Terada, T., Inui, K.
  • Journal Title: Pharmacol. 75(9)(REVIEW) Pages: 1689-1696
  • Peer Reviewed
• [Journal Article] Critical roles of Sp1 in gene expression of human and rat H^+/organic cation antiporters (MATE1). (2007)
  • Author(s): Kajiwara, M., Terada, T., Asaka, J., Ogasawara, K., Katsura, T.Ogawa, O., Fukatsu, A., Doi, T., Inui, K.
  • Journal Title: Am.J.Physiol.Renal Physiol. 293(5) Pages: F1564-F1570
  • Peer Reviewed
• [Journal Article] Hepatocyte nuclear factor-4a regulates the human organic anion transporter 1 gene in the kidney. (2007)
  • Author(s): Ogasawara, K., Terada, T., Asaka, J., Katsura, T., Inui, K.
  • Journal Title: Am.J.Physiol.Renal Physiol. 292(6) Pages: F1819-F1826
  • Peer Reviewed
• [Journal Article] Identification of essential histidine and cysteine residues of H^+/organic cation antiporter, Multidrug and Toxin Extrusion (MATE). (2007)
  • Author(s): Asaka, J., Terada, T., Tsuda, M., Katsura, T., Inui, K.
  • Journal Title: Mol.Pharmacol. 71(6) Pages: 1487-1493
  • Peer Reviewed
• [Journal Article] Characterization of the basal promoter element of human organic cation transporter 2 (hOCT2) gene. (2007)
  • Author(s): Asaka, J., Terada, T., Ogasawara, K., Katsura, T., Inui, K.
  • Journal Title: J.Pharmacol.Exp.Ther. 321(2) Pages: 684-689
  • Peer Reviewed
• [Journal Article] Oppositely-directed H+ gradient functions as a driving force of rat H+/organic cation antiporter. (2007)
  • Author(s): Tsuda, M., Terada, T., Asaka, J., Ueba, M., Katsura, T., Inui, K.
  • Journal Title: Am.J.Physiol.Renal Physiol. 292(2) Pages: F593-F598
  • Peer Reviewed
• [Journal Article] Gene expression and regulation of drug transporters in the intestine and kidney. (2007)
  • Author(s): Terada, T., Inui, K.
  • Journal Title: Biochem.Pharmacol. 73(3)(REVIEW) Pages: 440-449
  • Peer Reviewed
• [Presentation] 質の高いがん専門薬剤師の育成に向けて-京大病院での取り組み (2009)
  • Author(s): 寺田智祐、乾賢一
  • Organizer: 第19回日本医療薬学会年会
  • Place of Presentation: 長崎市
  • Year and Date: 2009-10-25
• [Presentation] 薬剤業務としてのUGT1A1遺伝子解析 (2009)
  • Author(s): 寺田智祐、乾賢一
  • Organizer: 日本病院薬剤師会関東ブロック第39回学術大会
  • Place of Presentation: 長野市
  • Year and Date: 2009-08-30
• [Presentation] Pathophysiological roles of renal organic anion transporter 3 (Oat3) in the cholestasis (2008)
  • Author(s): Terada, T., Chen, J., Ogasawara, K., Katsura, T., Inui, K.
  • Organizer: 2nd Asian Pacific Regional ISSX meeting
  • Place of Presentation: 上海
  • Year and Date: 20080511-20080513
• [Presentation] 薬物トランスポータの遺伝子発現制御 (2008)
  • Author(s): 寺田智祐、乾賢一
  • Organizer: 第23回日本薬物動態学会年会
  • Place of Presentation: 熊本
  • Year and Date: 2008-11-27
• [Presentation] 小腸及び腎薬物トランスポータの基礎と臨床 (2007)
  • Author(s): 寺田智祐、乾賢一
  • Organizer: 第1回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 東京都
  • Year and Date: 2007-12-16
• [Book] SLC15A1薬物トランスポータ活用ライブラリー(乾賢一編集) (2009)
  • Author(s): 寺田智祐
  • Total Pages: 36-39
  • Publisher: 羊土社
• [Book] SLC15A2薬物トランスポータ活用ライブラリー(乾賢一編集) (2009)
  • Author(s): 寺田智祐
  • Total Pages: 40-42
  • Publisher: 羊土社
• [Book] H^+/有機カチオンアンチポータ(MATE/SLC47A).AnnualReview腎臓2008(御手洗哲也、東原英二、秋澤忠男、五十嵐隆、金井好克編) (2008)
  • Author(s): 寺田智祐、乾賢一
  • Total Pages: 36-42
  • Publisher: 中外医学社
• [Book] Impact of drug transport proteins.(In Drug Absorption Studies-In Situ, In Vitro and In Silico Models, ed.)(C.Ehrhardt and K.Kim) (2008)
  • Author(s): Terada, T., Inui, K.
  • Total Pages: 559-576
  • Publisher: Springer, New York
• [Book] ペプチドトランスポータを介した薬物吸収の改善(薬剤師が変える薬物治療2,乾賢一監修編著) (2007)
  • Author(s): 寺田智祐
  • Total Pages: 194-199
  • Publisher: 京都大学医学部附属病院薬剤部