2006 Fiscal Year Final Research Report Summary
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 |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Mie University |
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Principal Investigator |
OKUDA Masahiro Mie University, Mie University Hospital, Professor, 医学部附属病院, 教授 (70252426)
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| Co-Investigator(Kenkyū-buntansha) |
MIZUTANI Hideki Mie University Hospital, Lecturer, 医学部附属病院, 講師 (80397504)
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| Project Period (FY) |
2005 – 2006
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| Keywords | organic cation transporter / renal proximal tubules / OCT2 / promoter / gender differences / testosterone / transcriptional regulation / basic drugs |
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| 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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[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
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Author(s)
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Transplant. Proc. 37-4
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Author(s)
Shimizu, Y., Masuda, S., Nishihara, K., Ji, L., Okuda, M., Inui, K.
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Journal Title
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