Distribution of Rat Organic Anion Transporting Polypeptide-E (oatp-E) in the Rat Eye

Ito, Aki; Yamaguchi, Katsuhiro; Tomita, Hiroshi; Suzuki, Takehiro; Onogawa, Tohru; Sato, Takeaki; Mizutamari, Hiroya; Mikkaichi, Tsuyoshi; Nishio, Takeshi; Suzuki, Takashi; Unno, Michiaki; Sasano, Hironobu; Abe, Takaaki; Tamai, Makoto

doi:10.1167/iovs.02-1108

Cited by 45 publications

(39 citation statements)

References 39 publications

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“…2). The band size at 75 kDa is similar to that of rat oatp3 detected in retina (Ito et al 2002). In contrast, no band was detected in the liver or kidney (Fig.…”

Section: Discussionsupporting

confidence: 69%

“…A carrier-mediated process, rather than passive diffusion, was reported to be involved in this plasma membrane transport process (Hennemann et al 2001). Since rat oatp3 has the 1 Dr Takaaki Abe and his coworkers (Tohoku University, Sendai, Japan) have demonstrated the localization of rat oatp3 in rat brain parenchymal cells close to the 3rd ventricle by means of immunohistochemical analysis using anti-rat oatp3 antibody (Ito et al 2002) in the 12th International Thyroid Congress at Kyoto, Japan (abstract SB-1). ability to transport T 3 and T 4 (Abe et al 1998), a likely function of oatp3 in the brain would be mediation of TH uptake into TH-sensitive neural cells.…”

Section: Discussionmentioning

confidence: 99%

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Localization of organic anion transporting polypeptide 3 (oatp3) in mouse brain parenchymal and capillary endothelial cells

Ohtsuki

Takizawa

Takanaga

et al. 2004

Journal of Neurochemistry

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Organic anion transporting polypeptide 3 (oatp3) transports various CNS-acting endogenous compounds, including thyroid hormones and prostaglandin E 2 , between extra-and intracellular spaces, suggesting a possible role in CNS function. The purpose of this study was to clarify the expression and localization of oatp3 in the mouse brain. RT-PCR analysis revealed that oatp3 mRNA is expressed in brain capillary-rich fraction, conditionally immortalized brain capillary endothelial cells, choroid plexus, brain and lung, but not in liver or kidney, where oatp1, 2 and 5 mRNAs were detected. Immunohistochemical analysis with anti-oatp3 antibody suggests that oatp3 protein is localized at the brush-border membrane of mouse choroid plexus epithelial cells. Furthermore, intense immunoreactivity was detected in neural cells in the border region between hypothalamus and thalamus, and in the olfactory bulb. Immunoreactivity was also detected in brain capillary endothelial cells in the cerebral cortex. These localizations in the mouse brain suggest that oatp3 plays roles in blood-brain and -cerebrospinal fluid barrier transport of organic anions and signal mediators, and in hormone uptake by neural cells. Keywords: blood-brain barrier, choroid plexus, hypothalamus, olfactory bulb, organic anion transporting polypeptide 3. Organic anion transporting polypeptide 3 (oatp3; Slc21a7) mediates sodium-independent transport of a wide variety of amphipathic organic compounds, including opioid peptides, neurosteroid conjugates, thyroid hormones (THs), bile acids and drugs, such as fexofenadine (Abe et al. 1998;Dresser et al. 2002;Hagenbuch and Meier 2003). Since many of these substrates are active in the CNS, oatp3 may play a role in the control of CNS functions.THs play an important role in normal CNS development and maturation. The expression of TH receptors was detected in adult brain (Puymirat et al. 1991), and hypothyroidism induces changes in the neuronal morphology of adult rat brain (Ruiz-Marcos et al. 1980) and affects memory in human patients (Burmeister et al. 2001). THs interact with nuclear TH receptors to express their effects. Although it was believed that THs enter target cells by passive diffusion, the recent reports have demonstrated that their cellular uptake by cells, including neurons and astrocytes, is carrier-mediated (Francon et al. 1989;Chantoux et al. 1995;Hennemann et al. 2001). Although roles of oatp family members in neural cells have not been considered yet, it is conceivable that oatps mediate TH uptake of the target cells in the brain.Expression of oatp3 mRNA in rat brain has been detected by means of RNase protection assay and RT-PCR analysis (Walters et al. 2000;Ohtsuki et al. 2003). Since oatp3 mediates transport of THs, such as triiodothyronine (T 3 ) and thyroxine (T 4 ) (Abe et al. 1998), we hypothesize that oatp3 is expressed at the neural cells and mediates their TH uptake. Received January 13, 2004; revised manuscript received March 19, 2004; accepted April 8, 2004.Address correspondence ...

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“…2). The band size at 75 kDa is similar to that of rat oatp3 detected in retina (Ito et al 2002). In contrast, no band was detected in the liver or kidney (Fig.…”

Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Localization of organic anion transporting polypeptide 3 (oatp3) in mouse brain parenchymal and capillary endothelial cells

Ohtsuki

Takizawa

Takanaga

et al. 2004

Journal of Neurochemistry

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“…luminal and abluminal [198], retinal pigmented epithelial cells, basolateral [198] rOATP2B1 retina [195] rOATP3A1 retina [195] rOATP4A1 retina [195,201] retina [201] human OCT1 retinal pigmented epithelium [202] OCT2 retina [194] 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 44 OCT3 retina [194] OCTN2 retina [194] rat rOCT1 retina [195]{ rOCT2 retina [195]{ mouse mOCT3 retinal pigmented epithelial cells [203] mOCTN1 blood retinal capillary epithelial cells [204] mOCTN2 blood retinal capillary epithelial cells [204] rat rOAT2 retina [195] rOAT3 retina [195], Blood retinal capillaries [205] primary cultured blood retinal capillary endothelial cells [205] blood retinal capillary endothelial cells: abluminal …”

Section: Drug Metabmentioning

confidence: 99%

Drug Transporters in the Central Nervous System

Stieger

Gao

2015

Clin Pharmacokinet

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Drug targets in the central nervous system (CNS) are numerous and important for drug therapy, e.g., of epilepsy or pain. Drugs and other xenobiotics as well as nutrients cannot freely cross the blood-brain barrier or freely enter cells across plasma membranes and therefore require transport systems. This overview summarizes the current knowledge on the expression of drug transporters in barriers shielding the CNS from the systemic circulation and as such controlling the pharmacokinetics of drugs in the CNS. The main drug transporter families covered are SLCO, SCL22A, ABCB, and ABCC, as genes of these families code for numerous drug transporters. While knowledge on messenger RNA expression in humans, rats, and mice is remarkable, there is clearly a gap in knowledge on the subcellular expression of transporters in specific cells in the CNS and in the barriers shielding the CNS from the systemic circulation. Recent methodologic developments including synthesis of drugs and endogenous substances for imaging will in the future allow the investigation of the function and physiologic role of transporters in the CNS including difficult-to-access systems such as the choroid plexus. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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“…Anti-transporter polyclonal antibody was prepared by immunizing rabbits with the peptide-keyhole limpet hemocyanin conjugate (Hokkaido System Science, Hokkaido, Japan). The peptides were 14 amino acids (CLGEKESEHTDVHG) for Oatp1, 26) 12 amino acids (CTEVLRSKVTED) for Oatp2, 27) 17 amino acids (CNGYYCVPYDEQSNETPL) for Oatp4 28) and 15 amino acids (CLQPGPGTHNGNIPP) for Ntcp. 29) Analysis of DNA-Binding Activity DNA-binding activities of HNF1 and HNF4a were measured with nuclear protein (10 mg) using a TransAM TM HNF family kit from Active Motif (CA, U.S.A.).…”

Section: Animals and Treatmentmentioning

confidence: 99%

Effect of Aminoguanidine on Lipopolysaccharide-Induced Changes in Rat Liver Transporters and Transcription Factors

Aoki

Nakajima

Hoshi

et al. 2008

Biological & Pharmaceutical Bulletin

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Lipopolysaccharide (LPS) administration in the rat produces a sepsis model of cholestasis which is directly associated with changes in the expression of several liver transporters.2) Among the various constitutively expressed influx (Ntcp, Oatp1, Oatp2, Oatp4, Oct1, Oat2, Oat3) and efflux transporters (Mrp2, Mrp3, Bsep, Mdr1a, Mdr1b) in rat liver, LPS down-regulates most of the influx and efflux transporters, but up-regulates some efflux transporters, including Mrp3 and Mdr1b. These changes are thought to represent a defense mechanism which protects the liver from the accumulation of endogenous compounds such as bile acid and bilirubin, as well as exogenous toxic compounds.With regard to mechanism, LPS induces the production of proinflammatory cytokines (cytokines), such as tumor necrosis factor (TNF)-a, interleukin (IL)-1b and IL-6 in Kupffer cells (KCs), and nitric oxide (NO) via the induction of NO synthase (iNOS) in KCs and hepatocytes. These cytokines are thought to be major mediators of the down-regulation of mRNA of transporters such as Ntcp, Oatp1, Oatp2, Mrp2, Mrp3, Bsep and Mdr1a, and of the up-regulation of Mdr1b. [3][4][5][6][7][8][9] Extensive studies of the molecular mechanisms of transporter regulation show that the LPS-induced downregulation of transporters is strongly affected by the preceding decrease in the quantity or function of nuclear transcription factors such as hepatocytes nuclear factors (HNF1a, HNF4a) and nuclear receptor heterodimers with retinoid X receptor (RXR)a (retinoic acid receptor (RAR))a, pregnane X receptor (PXR), farnesoid X receptor (FXR), constitutive ardrostane receptor (CAR)). 10)In contrast, relatively few studies have investigated the role of NO derived from iNOS in the regulation of hepatic transporters. Among studies to date, a regulatory role of NO on the mRNA of Oat2 was identified in in vivo experiments with LPS (1 mg/kg) and aminoguanidine (AG, 20 mg/kg, an iNOS inhibitor).11) On the contrary, AG (100 mg/kg) had no effect on LPS (4 mg/kg)-induced changes in rat liver transporter mRNA levels.2) Nevertheless, NO's effect in decreasing transcriptional activities of RXRa 12) and HNF4a 13) indicate its possible role as a mediator of transporter genes.Here, we investigated the role of iNOS-derived NO in the regulation of mRNA expression of rat liver transporters (Table 1; Ntcp, Oatp1, Oatp2, Oatp4, Oat2, Oat3, Oct1, Mrp2, Mrp3, Bsep, Mdr1a, Mdr1b) To determine the role of nitric oxide (NO) in rat liver transporter regulation, we investigated whether NO mediates lipopolysaccharide (LPS)-induced changes in transporters and their transcription factor expression using aminoguanidine (AG), an inhibitor of induced nitric oxide synthase (iNOS). We confirmed that LPS decreased mRNA levels for Ntcp, Oatp1, Oatp2, Oatp4, Oct1, Mrp2, Mdr1a and increased those for Mdr1b at 16 h after administration. AG attenuated these decreases for Ntcp, Oatp1 and Oatp4 (retinoid X receptor (RXR)a aand hepatocyte nuclear factor (HNF)4a a-dependent genes) and increase for Mdr1b (nuclear fact...

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Distribution of Rat Organic Anion Transporting Polypeptide-E (oatp-E) in the Rat Eye

Cited by 45 publications

References 39 publications

Localization of organic anion transporting polypeptide 3 (oatp3) in mouse brain parenchymal and capillary endothelial cells

Localization of organic anion transporting polypeptide 3 (oatp3) in mouse brain parenchymal and capillary endothelial cells

Drug Transporters in the Central Nervous System

Effect of Aminoguanidine on Lipopolysaccharide-Induced Changes in Rat Liver Transporters and Transcription Factors

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