{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC47A2 encodes the multidrug and toxin extrusion protein 2‐K (MATE2‐K), a proton/organic cation antiporter predominantly expressed at the apical (brush‐border) membranes of renal proximal tubular cells. It facilitates the secretion of a wide range of endogenous metabolites and exogenous compounds—including drugs such as metformin, tetraethylammonium, and certain anticancer agents—thereby contributing to renal detoxification and drug clearance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin the kidney, the activity of SLC47A2/MATE2‐K is tightly regulated by both extracellular and intracellular signals to adjust organic cation secretion in response to physiological demands. Rapid regulatory mechanisms—including modulation by intracellular signaling pathways and environmental factors such as fluid shear stress via redox‐sensitive Nrf2 signaling—have been shown to alter transporter activity. Moreover, coordinated expression and colocalization with other renal transporters (e.g. OCT2, OAT1/3) further enable an efficient and adaptable vectorial drug secretion system."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic variability in SLC47A2 can substantially influence MATE2‐K function. Several coding single nucleotide polymorphisms have been identified that either markedly reduce or—in rare cases—increase transporter activity, thereby affecting substrate handling of compounds such as metformin. In vitro studies using fluorescent probe substrates (e.g. DAPI) have demonstrated substrate‐dependent inhibition profiles and revealed clinically relevant interactions with inhibitors such as pazopanib. Although heterozygous variants sometimes do not show overt effects on drug disposition, these findings underscore the pharmacogenomic importance of SLC47A2 in drug–drug interactions and interindividual variability in therapeutic responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence also points to roles for SLC47A2/MATE2‐K outside of classic renal excretion. Notably, a brain‐specific gene coexpression network implicated MATE2 as a central ciliary gene, thereby hinting at potential functions in ciliary signaling and neurobiology. In addition, epigenetic repression of SLC47A2 has been observed in renal cell carcinoma, with altered chromatin modifications and regulatory noncoding RNAs contributing to its downregulation—a change that may serve as a negative prognostic marker. These observations broaden the clinical significance of SLC47A2 to include implications for cancer biology and possibly other organ systems."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "18"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yuko Tanihara, Satohiro Masuda, Tomoko Sato, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacogenet Genomics (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/FPC.0b013e328335639f"}], "href": "https://doi.org/10.1097/FPC.0b013e328335639f"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20016398"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20016398"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kin-ya Ohta, Katsuhisa Inoue, Tomoya Yasujima, et al. 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