2004 Fiscal Year Final Research Report Summary
Study of drug transport mechanism by renal organicion transporters and their clinical significance
| Project/Area Number |
15590858
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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 |
Kidney internal medicine
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| Research Institution | Kyorin University |
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Principal Investigator |
HOSOYAMADA Makoto Kyorin Univ., Sch.Med, Pharmacology & Toxicology, Lecture, 医学部, 講師 (00291659)
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| Co-Investigator(Kenkyū-buntansha) |
ANZAI Naohiko Kyorin Univ., Sch. Med., Pharmacology & Toxicology, Assistant Prof., 医学部, 助手 (70276054)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Organic anion transport / Drug transport / Kidney / Organic cation transport / Diuretics / Anti-arrhythmia |
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| Research Abstract |
1)Interactions of human- and rat-organic anion transporters with pravastatin and cimetidine
We have elucidated the interactions of human and rat organic anion transporters (hOATs and rOATs) with pravastatin and cimetidine. Pravastatin inhibited hOAT1/rOAT1, hOAT2/rOAT2, hOAT3/rOAT3, and hOAT4. The mode of inhibition was noncompetitive for hOAT1 and hOAT2, whereas it was competitive for hOAT3 and hOAT4. Cimetidine also inhibited hOAT1/rOAT1, hOAT3/rOAT3, and hOAT4. The mode of inhibition was a combination of competitive and noncompetitive manners for hOAT1, whereas it was competitive for hOAT3. The effects of OAT inhibitors on OAT1, OAT2, and OAT3 exhibited some but not so remarkable interspecies differences between humans and rats. In conclusion, we have characterized pravastatin and cimetidine as OAT inhibitors.
2)Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules
Human organic anion transporter OAT4 is expressed in the kidne
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y and placenta and mediates high-affinity transport of estrone-3-sulfate (E1S). Because a previous study demonstrated no trans-stimulatory effects by E1S, the mode of organic anion transport via OAT4 remains still unclear. In the present study, we examined the driving force of OAT4 using mouse proximal tubular cells stably expressing OAT4 (S2 OAT4). OAT4-mediated E1S uptake was inhibited by glutarate (GA) (IC50:1.25 mM) and [14C]GA uptake via S2 OAT4 was significantly trans-stimulated by unlabeled GA (5mM) (P<0.001). [3H]E1S uptake via S2 OAT4 was significantly trans-stimulated by preloaded GA (P<0.001) and its [14C]GA efflux was significantly trans-stimulated by unlabeled E1S in the medium (P<0.05). In addition, both the uptake and efflux of [14C]p-aminohippuric acid (PAH) and [14C]GA via S2 OAT4 were significantly trans-stimulated by unlabeled GA or PAH. The immunoreactivities of OAT4 were observed in the apical membrane of proximal tubules along with those of basolateral organic anion/dicarboxylate exchangers such as hOAT1 and hOAT3 in the same tubular population. These results indicate that OAT4 is an apical organic anion/dicarboxylate exchanger and mainly functions as an apical pathway for the reabsorption of some organic anions in renal proximal tubules driven by an outwardly directed dicarboxylate gradient. Less
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Research Products
(7 results)
