Evaluation and estimation of renal drug elimination based on promoter analyses of organic cation transporters
Project/Area Number |
17590119
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Medical pharmacy
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Research Institution | Mie University |
Principal Investigator |
OKUDA Masahiro Mie University, Mie University Hospital, Professor, 医学部附属病院, 教授 (70252426)
|
Co-Investigator(Kenkyū-buntansha) |
MIZUTANI Hideki Mie University Hospital, Lecturer, 医学部附属病院, 講師 (80397504)
|
Project Period (FY) |
2005 – 2006
|
Project Status |
Completed (Fiscal Year 2006)
|
Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
|
Keywords | organic cation transporter / renal proximal tubules / OCT2 / promoter / gender differences / testosterone / transcriptional regulation / basic drugs / アンドロゲン受容体 / 有機カチオントランスポータ / LLC-PK1 / nilutamide / rOCT2 / androgen response elements |
Research Abstract |
Organic cation transporter OCT2, expressed in the basolateral membranes of renal proximal tubules, is considered to mediates inter-and intra-individual variability of pharmacokinetics of basic drugs. However, mechanism of expressional regulation is scarcely known. In the present study, we analyzed the mechanism of testosterone-mediated regulation of OCT2 expression in detail, using deleted constructs and constructs with mutated AREs. 1. Cloning of promoter regions of OCT1, 2, and 3 Promoter regions of OCT1 and OCT3 were isolated by PCR using rat genomic DNA as a template and specific primers for OCT1 and OCT3. Promoter region of OCT2 was isolated by screening rat genomic library. 2. Stimulation of transcription of OCT2 by testosterone After insertion of each promoter region into pGL3 vector, it was introduced into LLC-PK1 cells, cultured renal epithelial cells derived from pig kidney, with rat androgen receptor. Promoter activity of OCT2 was stimulated by testosterone at 1 nM and higher, and was inhibited by nilutamide, an antagonist of androgen receptor. 3. Analyses of transcription activity using deleted constructs and constructs with mutated AREs Promoter activity was analyzed using deleted constructs and constructs with mutated ARE located in the promoter region of OCT2. As the conclusion, two distinct AREs, ARE-1 and ARE-3, were clarified to have relevant roles in the stimulation of transcription activity of OCT2 by testosterone.
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Report
(3 results)
Research Products
(28 results)
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[Journal Article] Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1.2005
Author(s)
Kimura, N., Masuda, S., Tanihara, Y., Ueo, H., Okuda, M., Katsura, T., Inui, K.
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Journal Title
Drug Metab. Pharmacokinet. 20-5
Pages: 379-386
NAID
Description
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[Journal Article] Initial dosage adjustment for oral administration of tacrolimus using the intestinal MDR1 level in living-donor liver transplant recipients.2005
Author(s)
Masuda, S., Goto, M., Okuda, M., Ogura, Y., Oike, F., Kiuchi, T., Tanaka, K., Inui, K.
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Journal Title
Transplant. Proc. 37-4
Pages: 1728-1729
Description
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[Journal Article] Increased protein level of PEPT1 intestinal H+-peptide cotransporter upregulates absorption of glycylsarcosine and ceftibuten in 5/6 nephrectomized rats..2005
Author(s)
Shimizu, Y., Masuda, S., Nishihara, K., Ji, L., Okuda, M., Inui, K.
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Journal Title
Am. J. Physiol. Gastrointest. Liver Physiol. 288-4
Description
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[Book] 医療薬学 第4版2005
Author(s)
奥田真弘
Total Pages
419
Publisher
廣川書店
Description
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