| Institution: | 1. Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, 274-8510, Japan;2. Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, 7943, USA;1. Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, 274-8510, Japan;2. Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, 7943, USA;1. Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan;2. Showa Pharmaceutical University, Machida, Japan;1. Division of Pharmaceutics, Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen Minato-ku, Tokyo, 105-8512, Japan;2. Division of Bioorganic and Medicinal Chemistry, Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen Minato-ku, Tokyo, 105-8512, Japan;1. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Japan;2. College of Pharmacy, Kinjo Gakuin University, Moriyama-ku, Nagoya, Japan;3. Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan |
| Abstract: | Using X. laevis oocyte expression system, we investigated whether human Na+-coupled monocarboxylate transporter 1 (SLC5A8, hSMCT1) is involved in 2,4-dichlorophenoxyacetate (2,4-D) uptake by the renal tubular epithelial cells. 2,4-D is a herbicide that causes nephrotoxicity. Heterologous expression of hSMCT1 in X. laevis oocytes conferred the ability to take up 2,4-D; the induced uptake process was Na+-dependent and electrogenic. The Na+-dependent uptake of 2,4-D was inhibited not only by known hSMCT1 substrates, but also by many structural analogs of 2,4-D. The currents induced by 2,4-D, 4-chlorophenoxyacetate (4-CPA) and 2-methyl-4-chlorophenoxyacetate (MCPA) were saturable: the rank order of the maximal induced current and the affinity for hSMCT1was 2,4-D > 4-CPA > MCPA. The relationship between the structures of the derivatives and their transport activity implied specific structural features in a compound for recognition as a substrate by hSMCT1. Furthermore, we have demonstrated using purified rabbit renal brush-border membrane vesicles that 2,4-D potently inhibited the Na+-dependent uptake of pyroglutamate, a typical substrate for Smct1, and that 2,4-D uptake process was Na+-dependent, saturable and inhibitable by a potent blocker, ibuprofen. We conclude that hSMCT1 is involved partially in the renal reabsorption of 2,4-D and its derivatives and their nephrotoxicity. |
