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Basic Science Investigations |
1 Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, Ibaraki, Japan
2 Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan
3 School of Health Sciences, Faculty of Medicine, Kanazawa University, Kanazawa, Japan
Recently, complementary DNA (cDNA) encoding a p-aminohippurate (PAH) transporter designated rat organic anion transporter 1 (OAT1) was isolated. OAT1, a multispecific organic anion transporter at the basolateral membrane, is exclusively expressed in the middle segment of the proximal tubule in the rat kidney. It has been proposed that OAT1 is indirectly involved in PAH uptake via the Na+ dicarboxylate cotransporter. In this study, in molecular biologic experiments using OAT1-expressing Xenopus laevis oocytes, we obtained evidence that 99mTc-mercaptoacetylglycylglycylglycine (MAG3) is transported via OAT1. Methods: Capped OAT1 complementary RNA (cRNA) was synthesized from library plasmid cDNA linearized with BamHI using in vitro transcription. Defolliculated oocytes were injected with 10 ng of OAT1 cRNA. Two to 3 d after injection, uptake of 99mTc-MAG3 was measured using ND96 solution containing 18.5 kBq of 99mTc-MAG3. Before the uptake experiments, OAT1-expressing oocytes were preincubated for 2 h with 1 mmol/L glutarate (a dicarboxylate), to generate an outwardly directed glutarate gradient. Then, after incubation for 60 min at room temperature, radioactivity of oocytes was determined. For the inhibition experiments, uptake was assessed in the absence or presence of inhibitor: 2 mmol/L of PAH, o-iodohippurate (OIH), probenecid, 3,5-diiodo-4-pyridone-N-acetate (iodopyracet), furosemide, ethacrynic acid, glucoheptonate, maleic acid, L-Tyr, or tetraethylammonium (TEA) or 0.1 mmol/L of 2,4-dinitrophenol (DNP). Results: Na+ had a significant effect on 99mTc-MAG3 uptake (P < 0.05). Accumulated glutarate stimulated simultaneous 99mTc-MAG3 uptake and glutarate excretion (P < 0.001). The following compounds significantly inhibited 99mTc-MAG3 uptake: PAH, 8.5% ± 16.2% of 99mTc-MAG3 uptake in the absence of an inhibitor; OIH, 26.4% ± 21.7%; probenecid, 29.1% ± 12.4%; iodopyracet, 15.8% ± 7.9%; furosemide, 30.5% ± 15.7%; ethacrynic acid, 21.6% ± 10.6%; glucoheptonate, 35.6% ± 22.6%; and maleic acid, 60.1% ± 18.7%. 99mTc-MAG3 accumulation in Xenopus laevis oocytes was not significantly inhibited by TEA, L-Tyr, or DNP. Conclusion: The following substances had a cis-inhibitory effect on 99mTc-MAG3 transport: PAH, OIH, probenecid, iodopyracet, furosemide, ethacrynic acid, and glucoheptonate. Glutarate had a trans-stimulative effect on 99mTc-MAG3 transport. 99mTc-MAG3 acts as a substrate of OAT1, an organic anion/dicarboxylate exchanger.
Key Words: 99mTc-MAG3 • organic anion transporter 1 • Xenopus laevis oocyte • membrane transport • renal function
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