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Hitoshi Endou - One of the best experts on this subject based on the ideXlab platform.
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Invited Review Molecular physiology of renal Organic Anion transporters
2016Co-Authors: Takashi Sekine, Hiroki Miyazaki, Hitoshi EndouAbstract:2006; doi:10.1152/ajprenal.00439.2004.—Recent advances in molecular biology have identified three Organic Anion transporter families: the Organic Anion trans-porter (OAT) family encoded by SLC22A, the Organic Anion transporting peptide (OATP) family encoded by SLC21A (SLCO), and the multidrug resistance-associ-ated protein (MRP) family encoded by ABCC. These families play critical roles in the transepithelial transport of Organic Anions in the kidneys as well as in other tissues such as the liver and brain. Among these families, the OAT family plays the central role in renal Organic Anion transport. Knowledge of these three families at the molecular level, such as substrate selectivity, tissue distribution, and gene localization, is rapidly increasing. In this review, we will give an overview of molecular information on renal Organic Anion transporters and describe recent topics such as the regulatory mechanisms and molecular physiology of urate transport. We will also discuss the physiological roles of each Organic Anion transporter in the light of the transepithelial transport of Organic Anions in the kidneys
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Novel liver-specific Organic Anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate†
Hepatology (Baltimore Md.), 2007Co-Authors: Ho Jung Shin, Naohiko Anzai, Hitoshi Endou, Kyung Kim, Atsushi Enomoto, Yoshikatsu KanaiAbstract:The liver plays an important role in the elimination of endogenous and exogenous lipophilic Organic compounds from the body, which is mediated by various carrier proteins that differ in substrate specificity and kinetic properties. Here, we have characterized a novel member of the Organic Anion transporter family (SLC22) isolated from human liver. The transporter named Organic Anion transporter 7 (OAT7/ SLC22A9) showed 35% to 46% identities to those of other Organic Anion transporters of SLC22 family. When expressed in Xenopus oocytes, OAT7 mediated Na+-independent, high-affinity transport of sulfate-conjugated steroids, estrone sulfate (ES; Km = 8.7 μM), and dehydroepiandrosterone sulfate (Km = 2.2 μM). In addition, OAT7 interacted with negatively charged sulfobromophthalein, indocyanine green, and several sulfate-conjugated xenobiotics. In contrast, glucuronide and glutathione conjugates exhibited no inhibitory effects on OAT7-mediated [3H]ES transport. OAT7-mediated [3H]ES transport was trans-stimulated by three-carbon to five-carbon (C3 to C5) short-chain fatty acids. The efflux of [14C]butyrate (C4) via OAT7 was significantly trans-stimulated by extracellular ES. Furthermore, OAT7 mediated [14C]butyrate uptake and [3H]ES efflux in exchange for extracellular butyrate both in Xenopus oocytes and OAT7-stably expressing cells. OAT7 protein was localized in the sinusoidal membrane of hepatocytes by immunohistochemical analysis. Conclusion: OAT7 is the first liver-specific transporter among members of the Organic Anion transporters of SLC22 family. Our findings suggest a new class of substrates for Organic Anion transporters and provide evidence for the transport of Anionic substances such as sulfate-conjugates in exchange for butyrate in hepatocytes. (HEPATOLOGY 2007;45:1046–1055.)
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molecular physiology of renal Organic Anion transporters
American Journal of Physiology-renal Physiology, 2006Co-Authors: Takashi Sekine, Hiroki Miyazaki, Hitoshi EndouAbstract:Recent advances in molecular biology have identified three Organic Anion transporter families: the Organic Anion transporter (OAT) family encoded by SLC22A, the Organic Anion transporting peptide (...
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Organic Anion transporter family: current knowledge.
Journal of pharmacological sciences, 2006Co-Authors: Naohiko Anzai, Yoshikatsu Kanai, Hitoshi EndouAbstract:Organic Anion transporters (OATs) play an essential role in the elimination of numerous endogenous and exogenous Organic Anions from the body. The renal OATs contribute to the excretion of many drugs and their metabolites that are important in clinical medicine. Several families of multispecific Organic Anion and cation transporters, including OAT family transporters, have recently been identified by molecular cloning. The OAT family consists of six isoforms (OAT1 - 4, URAT1, and rodent Oat5) and they are all expressed in the kidney, while some are also expressed in the liver, brain, and placenta. The OAT family represents mainly the renal secretory and reabsorptive pathway for Organic Anions and is also involved in the distribution of Organic Anions in the body, drug-drug interactions, and toxicity of Anionic substances such as nephrotoxic drugs and uremic toxins. In this review, current knowledge of and recent progress in the understanding of several aspects of OAT family members are discussed.
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human Organic Anion transporter 4 is a renal apical Organic Anion dicarboxylate exchanger in the proximal tubules
Journal of Pharmacological Sciences, 2004Co-Authors: Sophapun Ekaratanawong, Promsuk Jutabha, Naohiko Anzai, Yoshikatsu Kanai, Michio Takeda, Hiroki Miyazaki, Rie Noshiro, Samaisukh Sophasan, Hitoshi EndouAbstract:Human Organic Anion transporter OAT4 is expressed in the kidney 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 (5 mM) (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.
Peter J Meier - One of the best experts on this subject based on the ideXlab platform.
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Localization of Organic Anion transporting polypeptides in the rat and human ciliary body epithelium
Experimental Eye Research, 2004Co-Authors: Robert Huber, Andreas Wenzel, Stephan R. Vavricka, Manfred G. Ismair, Charlotte E. Remé, Peter J MeierAbstract:PURPOSE: To identify and localize the expression of multispecific Organic Anion transporting polypeptides (Oatps/OATPs) in the ciliary body epithelium and to investigate their possible involvement in the transport of the antiglaucoma agent unoprostone. METHODS: Oatps/OATPs were detected by immunoblot analysis and by immunofluorescence microscopy in homogenized and fixed rat and human ciliary body samples using specific polyclonal antibodies. Transport of 3H-labelled unoprostone was measured in Oatp/OATP expressing Xenopus laevis oocytes. RESULTS: Immunoblots of ciliary body extracts were positive for rat Oatp1a4, Oatp1a5 and Oatp1b2 and for human OATP1A2, OATP1C1, OATP2B1, OATP3A1 and OATP4A1. Confocal immunofluorescence microscopy localized Oatp1a4 and Oatp1b2 as well as all immunoblot positive human OATPs at the basolateral plasma membrane of the non-pigmented rat and human ciliary body epithelium, respectively. However, for human OATPs additional regional differences in expression were found with OATP1A2 and OATP1C1 being expressed only in the pars plana of human ciliary body epithelium. Furthermore, OATP1C1, OATP3A1 and OATP4A1 were also expressed at the basolateral plasma membrane of the pars plana pigmented epithelium. And finally, deesterified unoprostone carboxylate was found to be transported by OATP1A2, OATP2B1 and OATP4A1 with approximate K(m)-values of 93, 91 and 132 microm, respectively. CONCLUSIONS: Several multispecific Organic Anion transporting polypeptides are expressed at the basolateral plasma membrane of the non-pigmented, and to a lesser extent also of the pigmented, epithelium in rat and human ciliary body. These Oatps/OATPs can account for the previously suggested 'liver-like' transport functions of mammalian ciliary body epithelium.
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The superfamily of Organic Anion transporting polypeptides
Biochimica et Biophysica Acta, 2003Co-Authors: Bruno Hagenbuch, Peter J MeierAbstract:Organic Anion transporting polypeptides (Oatps/OATPs) form a growing gene superfamily and mediate transport of a wide spectrum of amphipathic Organic solutes. Different Oatps/OATPs have partially overlapping and partially distinct substrate preferences for Organic solutes such as bile salts, steroid conjugates, thyroid hormones, Anionic oligopeptides, drugs, toxins and other xenobiotics. While some Oatps/OATPs are preferentially or even selectively expressed in one tissue such as the liver, others are expressed in multiple organs including the blood-brain barrier (BBB), choroid plexus, lung, heart, intestine, kidney, placenta and testis. This review summarizes the actual state of the rapidly expanding OATP superfamily and covers the structural properties, the genomic classification, the phylogenetic relationships and the functional transport characteristics. In addition, we propose a new species independent and open ended nomenclature and classification system, which is based on divergent evolution and agrees with the guidelines of the Human Genome Nomenclature Committee.
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interactions of rifamycin sv and rifampicin with Organic Anion uptake systems of human liver
Hepatology, 2002Co-Authors: Stephan R. Vavricka, Peter J Meier, Jessica E Van Montfoort, Karin FattingerAbstract:The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and rifampicin were shown to interfere with hepatic Organic Anion uptake by inhibition of the Organic Anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human Organic Anion transporting polypeptide C (SLC21A6) (OATP-C), human Organic Anion transporting polypeptide 8 (SLC21A8) (OATP8), human Organic Anion transporting polypeptide B (SLC21A9) (OATP-B), and human Organic Anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic Organic Anion elimination.
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original articlesinteractions of rifamycin sv and rifampicin with Organic Anion uptake systems of human liver
Hepatology, 2002Co-Authors: Stephan R. Vavricka, Peter J Meier, Jessica E Van Montfoort, Karin FattingerAbstract:The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and rifampicin were shown to interfere with hepatic Organic Anion uptake by inhibition of the Organic Anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 μmol/L) cis-inhibited human Organic Anion transporting polypeptide C (SLC21A6) (OATP-C), human Organic Anion transporting polypeptide 8 (SLC21A8) (OATP8), human Organic Anion transporting polypeptide B (SLC21A9) (OATP-B), and human Organic Anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 μmol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate Ki values were 2 μmol/L for OATP-C, 3 μmol/L for OATP8, 3 μmol/L for OATP-B and 11 μmol/L for OATP-A. Rifampicin (10 μmol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C–, OATP-B–, and OATP-A–mediated BSP transport was below 15%. 100 μmol/L rifampicin inhibited OATP-C– and OATP8-, OATP-B– and OATP-A–mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding Ki values were 17 μmol/L for OATP-C, 5 μmol/L for OATP8, and 51 μmol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent Km value 13 μmol/L) and OATP8 (2.3 μmol/L). In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic Organic Anion elimination. (HEPATOLOGY 2002;36:164-172.)
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identification of Organic Anion transporting polypeptide 4 oatp4 as a major full length isoform of the liver specific transporter 1 rlst 1 in rat liver
FEBS Letters, 2000Co-Authors: Bruno Stieger, Bruno Hagenbuch, Valentino Cattori, Niels Hagenbuch, Kaspar E Winterhalter, Peter J MeierAbstract:A novel Organic Anion transporting polypeptide (Oatp)4(1) was isolated from rat liver that is 35 amino acids longer than the reported rat liver specific Organic Anion transporter (rlst)-1 and exhibits a 64% amino acid sequence identity with the human OATP-C (LST-1/OATP2; gene symbol SLC21A6). When expressed in Xenopus laevis oocytes, Oatp4 (Slc21a10) mediated polyspecific uptake of a variety of Organic Anions including taurocholate (K(m) approximately 27 microM), bromosulfophthalein (K(m) approximately 1.1 microM) and steroid conjugates. Based on nuclease protection analysis Oatp4 appears to be the predominant transcript in rat liver indicating that rlst-1 plays a minor role in overall hepatic Organic Anion uptake.
Douglas H. Sweet - One of the best experts on this subject based on the ideXlab platform.
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Organic Anion transporter 3 oat3 slc22a8 knockout mice exhibit altered clearance and distribution of penicillin g
American Journal of Physiology-renal Physiology, 2007Co-Authors: Adam L Vanwert, Rachel M Bailey, Douglas H. SweetAbstract:The interaction of renal basolateral Organic Anion transporter 3 (Oat3) with commonly used pharmacotherapeutics (e.g., NSAIDs, β-lactams, and methotrexate) has been studied extensively in vitro. Ho...
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Transport of estrone sulfate by the novel Organic Anion transporter Oat6 (Slc22a20)
American journal of physiology. Renal physiology, 2006Co-Authors: Gloriane Schnabolk, Geri L. Youngblood, Douglas H. SweetAbstract:Recently, a novel Slc22 gene family member expressed in murine olfactory mucosa was identified and based on sequence homology proposed to be an Organic Anion transporter [Oat6 (Slc22a20); J. C. Mon...
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Organic Anion transporter slc22a family members as mediators of toxicity
Toxicology and Applied Pharmacology, 2005Co-Authors: Douglas H. SweetAbstract:Exposure of the body to toxic Organic Anions is unavoidable and occurs from both intentional and unintentional sources. Many hormones, neurotransmitters, and waste products of cellular metabolism, or their metabolites, are Organic Anions. The same is true for a wide variety of medications, herbicides, pesticides, plant and animal toxins, and industrial chemicals and solvents. Rapid and efficient elimination of these substances is often the body's best defense for limiting both systemic exposure and the duration of their pharmacological or toxicological effects. For Organic Anions, active transepithelial transport across the renal proximal tubule followed by elimination via the urine is a major pathway in this detoxification process. Accordingly, a large number of Organic Anion transport proteins belonging to several different gene families have been identified and found to be expressed in the proximal nephron. The function of these transporters, in combination with the high volume of renal blood flow, predisposes the kidney to increased toxic susceptibility. Understanding how the kidney mediates the transport of Organic Anions is integral to achieving desired therapeutic outcomes in response to drug interactions and chemical exposures, to understanding the progression of some disease states, and to predicting the influence of genetic variation upon these processes. This review will focus on the Organic Anion transporter (OAT) family and discuss the known members, their mechanisms of action, subcellular localization, and current evidence implicating their function as a determinant of the toxicity of certain endogenous and xenobiotic agents.
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stoichiometry of Organic Anion dicarboxylate exchange in membrane vesicles from rat renal cortex and hoat1 expressing cells
American Journal of Physiology-renal Physiology, 2003Co-Authors: Amy G. Aslamkhan, Douglas H. Sweet, Yonghae Han, Ramsey Walden, John B. PritchardAbstract:Although membrane vesicle studies have established the driving forces that mediate renal Organic Anion secretion and the Organic Anion transporter Oat1 has now been cloned in several species, its s...
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Organic Anion transporter 3 slc22a8 is a dicarboxylate exchanger indirectly coupled to the na gradient
American Journal of Physiology-renal Physiology, 2003Co-Authors: Douglas H. Sweet, David S Miller, Ramsey Walden, Lauretta M S Chan, Xiaoping Yang, John B. PritchardAbstract:Basolateral uptake of Organic Anions in renal proximal tubule cells is indirectly coupled to the Na+ gradient through Na+-dicarboxylate cotransport and Organic Anion/dicarboxylate exchange. One mem...
Takashi Sekine - One of the best experts on this subject based on the ideXlab platform.
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Invited Review Molecular physiology of renal Organic Anion transporters
2016Co-Authors: Takashi Sekine, Hiroki Miyazaki, Hitoshi EndouAbstract:2006; doi:10.1152/ajprenal.00439.2004.—Recent advances in molecular biology have identified three Organic Anion transporter families: the Organic Anion trans-porter (OAT) family encoded by SLC22A, the Organic Anion transporting peptide (OATP) family encoded by SLC21A (SLCO), and the multidrug resistance-associ-ated protein (MRP) family encoded by ABCC. These families play critical roles in the transepithelial transport of Organic Anions in the kidneys as well as in other tissues such as the liver and brain. Among these families, the OAT family plays the central role in renal Organic Anion transport. Knowledge of these three families at the molecular level, such as substrate selectivity, tissue distribution, and gene localization, is rapidly increasing. In this review, we will give an overview of molecular information on renal Organic Anion transporters and describe recent topics such as the regulatory mechanisms and molecular physiology of urate transport. We will also discuss the physiological roles of each Organic Anion transporter in the light of the transepithelial transport of Organic Anions in the kidneys
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molecular physiology of renal Organic Anion transporters
American Journal of Physiology-renal Physiology, 2006Co-Authors: Takashi Sekine, Hiroki Miyazaki, Hitoshi EndouAbstract:Recent advances in molecular biology have identified three Organic Anion transporter families: the Organic Anion transporter (OAT) family encoded by SLC22A, the Organic Anion transporting peptide (...
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The multispecific Organic Anion transporter family: properties and pharmacological significance.
Trends in pharmacological sciences, 2004Co-Authors: Hiroki Miyazaki, Takashi Sekine, Hitoshi EndouAbstract:Physiological and pharmacological studies indicate that the renal and hepatic Organic Anion transport systems are responsible for the elimination of numerous compounds, such as drugs, environmental substances and metabolites of both endogenous and exogenous origins. Recently, the molecular identity of the Organic Anion transport system, the OAT family, was revealed. To date, six OAT members have been identified and shown to have important roles not only in detoxification in the kidneys, liver and brain, but also in the reabsorption of essential compounds such as urate. The OAT family members are closely associated with the pharmacokinetics, drug–drug interactions and toxicity of Anionic substances such as nephrotoxic drugs and uremic toxins. The molecular characterization of the OAT family encoded by SLC22A will be discussed.
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role of Organic Anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity
Journal of The American Society of Nephrology, 2002Co-Authors: Atsushi Enomoto, Takashi Sekine, Seok Ho Cha, Michio Takeda, Akihiro Tojo, Suparat Khamdang, Fumio Takayama, Isao Aoyama, Sakurako Nakamura, Hitoshi EndouAbstract:In uremic patients, various uremic toxins are accumulated and exert various biologic effects on uremia. Indoxyl sulfate (IS) is one of uremic toxins that is derived from dietary protein, and serum levels of IS are markedly increased in both uremic rats and patients. It has been previously reported that the accumulation of IS promotes the progression of chronic renal failure (CRF). This study demonstrates the role of rat Organic Anion transporters (rOATs) in the transport of IS and the induction of its nephrotoxicity. The administration of IS to 5/6-nephrectomized rats caused a faster progression of CRF, and immunohistochemistry revealed that IS was detected in the proximal and distal tubules where rOAT1 (proximal tubules) and/or rOAT3 (proximal and distal tubules) were also shown to be localized. In in vitro study, the proximal tubular cells derived from mouse that stably express rOAT1 (S2 rOAT1) and rOAT3 (S2 rOAT3) were established. IS inhibited Organic Anion uptake by S2 rOAT1 and S2 rOAT3, and the Ki values were 34.2 and 74.4 microM, respectively. Compared with mock, S2 rOAT1 and S2 rOAT3 exhibited higher levels of IS uptake, which was inhibited by probenecid and cilastatin, Organic Anion transport inhibitors. The addition of IS induced a decrease in the viability of S2 rOAT1 and S2 rOAT3 as compared with the mock, which was rescued by probenecid. These results suggest that rOAT1 and rOAT3 play an important role in the transcellular transport of IS and the induction of its nephrotoxicity.
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regulation by protein kinase c of Organic Anion transport driven by rat Organic Anion transporter 3 roat3
Life Sciences, 2000Co-Authors: Michio Takeda, Takashi Sekine, Hitoshi EndouAbstract:Abstract The Organic Anion transporter 3 (rOAT3) is a multispecific OAT localized at the basolateral membrane of the proximal tubule. The purpose of this study was to elucidate the role of protein kinase C (PKC) in the regulation of Organic Anion transport driven by rOAT3 and its mechanism of action. For this purpose, we established and utilized cells derived from the second segment of proximal tubule from mice stably expressing rOAT3 (S2 rOAT3). Phorbol 12-myristate 13-aceate (PMA), a PKC stimulator, attenuated the cellular uptake of estrone sulfate (ES), a prototype Organic Anion for rOAT3, in a dose- and time-dependent manner. PMA treatment resulted in a decrease in the Vmax, but not the Km of uptake of ES in S2 rOAT3. Treatment of S2 rOAT3 with other PKC stimulators or diacylglycerols also inhibited the uptake of ES, whereas that with an inactive phorbol ester did not. Chelerythrine chloride, a PKC inhibitor, reversed the PMA-induced decrease in uptake of ES in S2 rOAT3. These results suggest that PKC activation downregulates rOAT3-mediated Organic Anion transport. This downregulation may be due to the inhibition of translocation or internalization of the rOAT3 protein, resulting in the decrease in the Vmax of rOAT3-medaited Organic Anion transport.
Bruno Hagenbuch - One of the best experts on this subject based on the ideXlab platform.
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oatps oats and octs the Organic Anion and cation transporters of the slco and slc22a gene superfamilies
British Journal of Pharmacology, 2012Co-Authors: Megan Roth, Amanda Obaidat, Bruno HagenbuchAbstract:The human Organic Anion and cation transporters are classified within two SLC superfamilies. Superfamily SLCO (formerly SLC21A) consists of Organic Anion transporting polypeptides (OATPs), while the Organic Anion transporters (OATs) and the Organic cation transporters (OCTs) are classified in the SLC22A superfamily. Individual members of each superfamily are expressed in essentially every epithelium throughout the body, where they play a significant role in drug absorption, distribution and elimination. Substrates of OATPs are mainly large hydrophobic Organic Anions, while OATs transport smaller and more hydrophilic Organic Anions and OCTs transport Organic cations. In addition to endogenous substrates, such as steroids, hormones and neurotransmitters, numerous drugs and other xenobiotics are transported by these proteins, including statins, antivirals, antibiotics and anticancer drugs. Expression of OATPs, OATs and OCTs can be regulated at the protein or transcriptional level and appears to vary within each family by both protein and tissue type. All three superfamilies consist of 12 transmembrane domain proteins that have intracellular termini. Although no crystal structures have yet been determined, combinations of homology modelling and mutation experiments have been used to explore the mechanism of substrate recognition and transport. Several polymorphisms identified in members of these superfamilies have been shown to affect pharmacokinetics of their drug substrates, confirming the importance of these drug transporters for efficient pharmacological therapy. This review, unlike other reviews that focus on a single transporter family, briefly summarizes the current knowledge of all the functionally characterized human Organic Anion and cation drug uptake transporters of the SLCO and the SLC22A superfamilies. LINKED ARTICLES BJP recently published a themed section on Transporters. To view the papers in this section visit http://dx.doi.org/10.1111/bph.2011.164.issue-7
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xenobiotic transporters of the human Organic Anion transporting polypeptides oatp family
Xenobiotica, 2008Co-Authors: Bruno Hagenbuch, C GuiAbstract:1. The Organic Anion transporting polypeptides (humans OATP; other species Oatp) belong to the SLCO gene superfamily of transporters and are twelve transmembrane domain glycoproteins expressed in various epithelial cells. Some OATPs/Oatps are expressed in a single organ, while others are expressed ubiquitously. 2. The functionally characterized members mediate sodium-independent transport of a variety of structurally independent, mainly amphipathic Organic compounds, including bile salts, hormones and their conjugates, toxins, and various drugs. 3. This review summarizes the general features and the substrates of the eleven human OATPs. Furthermore, it reviews what is known about the mechanism of their multispecificity, their predicted structure, their role in drug-food interactions, and their role in cancer. 4. Finally, some open questions are raised that need to be addressed to advance OATP research in the near future.
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cellular entry of thyroid hormones by Organic Anion transporting polypeptides
Best Practice & Research Clinical Endocrinology & Metabolism, 2007Co-Authors: Bruno HagenbuchAbstract:Several transporter families that can transport thyroid hormones have been identified. One of these is represented by the Organic Anion transporting polypeptide (OATP) gene superfamily, classified within the solute carrier family SLCO. In humans, eleven different OATPs are expressed in various tissues, including the liver, kidney, brain, lung, intestine and placenta. They mediate sodium-independent transport of a variety of amphipathic Organic compounds, including thyroid hormones, bile acids, steroid hormones and their conjugates, linear and cyclic peptides, prostaglandins, numerous drugs and other xenobiotics. OATP1C1, which is expressed in the blood–brain barrier and testes, is the thyroid hormone transporter with the highest apparent affinity, with Km values of 90.4 nM for thyroxine (T4) and 127.7 nM for reverse T3 (rT3) transport, and could be essential for thyroid hormone delivery to the developing brain. OATP4A1 is expressed in the placenta and could be important for maternal thyroid hormone transport to the developing fetus.
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The superfamily of Organic Anion transporting polypeptides
Biochimica et Biophysica Acta, 2003Co-Authors: Bruno Hagenbuch, Peter J MeierAbstract:Organic Anion transporting polypeptides (Oatps/OATPs) form a growing gene superfamily and mediate transport of a wide spectrum of amphipathic Organic solutes. Different Oatps/OATPs have partially overlapping and partially distinct substrate preferences for Organic solutes such as bile salts, steroid conjugates, thyroid hormones, Anionic oligopeptides, drugs, toxins and other xenobiotics. While some Oatps/OATPs are preferentially or even selectively expressed in one tissue such as the liver, others are expressed in multiple organs including the blood-brain barrier (BBB), choroid plexus, lung, heart, intestine, kidney, placenta and testis. This review summarizes the actual state of the rapidly expanding OATP superfamily and covers the structural properties, the genomic classification, the phylogenetic relationships and the functional transport characteristics. In addition, we propose a new species independent and open ended nomenclature and classification system, which is based on divergent evolution and agrees with the guidelines of the Human Genome Nomenclature Committee.
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identification of Organic Anion transporting polypeptide 4 oatp4 as a major full length isoform of the liver specific transporter 1 rlst 1 in rat liver
FEBS Letters, 2000Co-Authors: Bruno Stieger, Bruno Hagenbuch, Valentino Cattori, Niels Hagenbuch, Kaspar E Winterhalter, Peter J MeierAbstract:A novel Organic Anion transporting polypeptide (Oatp)4(1) was isolated from rat liver that is 35 amino acids longer than the reported rat liver specific Organic Anion transporter (rlst)-1 and exhibits a 64% amino acid sequence identity with the human OATP-C (LST-1/OATP2; gene symbol SLC21A6). When expressed in Xenopus laevis oocytes, Oatp4 (Slc21a10) mediated polyspecific uptake of a variety of Organic Anions including taurocholate (K(m) approximately 27 microM), bromosulfophthalein (K(m) approximately 1.1 microM) and steroid conjugates. Based on nuclease protection analysis Oatp4 appears to be the predominant transcript in rat liver indicating that rlst-1 plays a minor role in overall hepatic Organic Anion uptake.