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Emi Nakashima - One of the best experts on this subject based on the ideXlab platform.
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6 mercaptopurine transport by equilibrative nucleoside transporters in conditionally immortalized rat syncytiotrophoblast cell lines tr tbts
Journal of Pharmaceutical Sciences, 2011Co-Authors: Emi Nakashima, Sumio Ohtsuki, Young-sook KangAbstract:Abstract Recently, more women were provided with 6-mercaptopurine (6-MP) during pregnancy. Therefore, we attempted to clarify the transport mechanisms of 6-MP through Blood–Placenta Barrier using rat conditionally immortalized syncytiotrophoblast cell lines (TR-TBTs). The uptake of 6-MP was time- and ATP dependent, but sodium independent in TR-TBTs. 6-MP was eliminated over 50% from the cells within 30min. The uptake of 6-MP was saturable with Michaelis–Menten constant values of 198 μM and 250 μM in TR-TBT 18d-1 and TR-TBT 18d-2, respectively. 6-Thioguanine, azathioprine, and hypoxantine, structural analogues of 6-MP, strongly inhibited [ 14 C]6-MP uptake. Equilibrative nucleoside transporter (ENT) inhibitors, adenosine and uridine, significantly inhibited [ 14 C]6-MP uptake. However, several organic anions and cations had no effect on [ 14 C]6-MP uptake in TR-TBTs. These results suggest that sodium-independent transporters, ENTs, may be involved in 6-MP uptake at the Placenta. In addition, multidrug resistance protein (MRP) inhibitors, methotrexate, probenecid, cefmetazole, and sulfinpyrazone, significantly increased the accumulation of [ 14 C]6-MP in the cells. It is indicated that 6-MP may be eliminated across the Blood–Placental Barrier via MRPs. TR-TBTs expressed mRNA of ENT1, ENT2, MRP4, and MRP5. These findings are important for the therapy of acute lymphoblastic leukemia and autoimmune diseases of pregnant women, and should be useful data in elucidating teratogenicity of 6-MP during pregnancy. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3773–3782, 2011
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influx mechanism of 2 3 dideoxyinosine and uridine at the Blood Placenta Barrier
Placenta, 2009Co-Authors: Kazuko Sato, Yoshimichi Sai, Tomohiro Nishimura, Noriko Kose, Takuya Chishu, S. Shimpo, Emi NakashimaAbstract:Abstract The Blood–Placenta Barrier (BPB) serves to protect the fetus from exposure to toxins, and to transport various nutrients, including nucleosides, and hormones from mother to fetus. It is known that nucleoside transporters contribute to the transfer of nucleosides and nucleoside analogues. 2′,3′-Dideoxyinosine (ddI) has a nucleoside structure, and crosses the BPB. Although ddI is a substrate of several transporters, including equilibrative nucleoside transporters (ENT1 and ENT2), the transport mechanism of ddI in the Placenta has not yet been characterized. Therefore, the purpose of this study was to clarify the influx mechanisms of ddI from the maternal to the fetal side, and to examine the interaction between ddI and uridine transport at the BPB. We studied ddI and uridine uptakes using a conditionally immortalized rat syncytiotrophoblast cell line, TR-TBT 18d-1, as a BPB model. The ddI uptake was temperature-dependent, Na+-independent and saturable. Kinetic analysis yielded Km values for ddI and uridine of 6.51 mM and 23.4 μM, respectively. Uridine uptake was inhibited by ENT1 and ENT2 substrates, and ddI uptake was also inhibited by substrates or inhibitors at concentrations that inhibit ENT2. Uridine uptake in Xenopus laevis oocytes expressing rat ENT2 was inhibited by 5 mM ddI, in agreement with the results for TR-TBT 18d-1. Our results indicate that ddI and uridine are both taken up in part via ENT2 in TR-TBT 18d-1 cells, and therefore that ENT2 may contribute to their uptake at the BPB.
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Influx Mechanism of 2′,3′-Dideoxyinosine and Uridine at the Blood–Placenta Barrier
Placenta, 2009Co-Authors: Kazuko Sato, Yoshimichi Sai, Tomohiro Nishimura, Noriko Kose, Takuya Chishu, S. Shimpo, Emi NakashimaAbstract:Abstract The Blood–Placenta Barrier (BPB) serves to protect the fetus from exposure to toxins, and to transport various nutrients, including nucleosides, and hormones from mother to fetus. It is known that nucleoside transporters contribute to the transfer of nucleosides and nucleoside analogues. 2′,3′-Dideoxyinosine (ddI) has a nucleoside structure, and crosses the BPB. Although ddI is a substrate of several transporters, including equilibrative nucleoside transporters (ENT1 and ENT2), the transport mechanism of ddI in the Placenta has not yet been characterized. Therefore, the purpose of this study was to clarify the influx mechanisms of ddI from the maternal to the fetal side, and to examine the interaction between ddI and uridine transport at the BPB. We studied ddI and uridine uptakes using a conditionally immortalized rat syncytiotrophoblast cell line, TR-TBT 18d-1, as a BPB model. The ddI uptake was temperature-dependent, Na+-independent and saturable. Kinetic analysis yielded Km values for ddI and uridine of 6.51 mM and 23.4 μM, respectively. Uridine uptake was inhibited by ENT1 and ENT2 substrates, and ddI uptake was also inhibited by substrates or inhibitors at concentrations that inhibit ENT2. Uridine uptake in Xenopus laevis oocytes expressing rat ENT2 was inhibited by 5 mM ddI, in agreement with the results for TR-TBT 18d-1. Our results indicate that ddI and uridine are both taken up in part via ENT2 in TR-TBT 18d-1 cells, and therefore that ENT2 may contribute to their uptake at the BPB.
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Enhancement of Zidovudine Uptake by Dehydroepiandrosterone Sulfate in Rat Syncytiotrophoblast Cell Line TR-TBT 18d-1
Drug metabolism and disposition: the biological fate of chemicals, 2008Co-Authors: Tomohiro Nishimura, Yoshimichi Sai, Noriko Kose, Kazuko Sato, Takuya Chishu, Young-sook Kang, Yoshiaki Seki, Tetsuya Terasaki, Emi NakashimaAbstract:AZT (3'-azido-3'-deoxythymidine; zidovudine), which is used for the prevention of mother-to-child transmission of HIV-1, is transPlacentally transferred to the fetus across the Blood-Placenta Barrier, which is composed of syncytiotrophoblasts. We recently showed that apical uptake of AZT by syncytiotrophoblasts is mediated by saturable transport system(s) in the TR-TBT 18d-1 cell line, and the cellular accumulation of AZT was increased in the presence of dehydroepiandrosterone sulfate (DHEAS). Here, we aimed to clarify the mechanism of this effect of DHEAS. Inhibitors of efflux transporters, including breast cancer resistance protein, P-glycoprotein, and multidrug resistance proteins, had little effect on the cellular accumulation of AZT in TR-TBT 18d-1. Kinetic study revealed that the rate constant for AZT uptake was greatly increased in the presence of 1 mM DHEAS. These results suggested that the effect of DHEAS was because of enhancement of the uptake process(es), rather than inhibition of efflux. When AZT uptake was analyzed according to the Michaelis-Menten equation, the estimated Michaelis constant, Km, for AZT uptake in the presence of 1 mM DHEAS was lower than that in its absence, whereas maximum uptake velocity, Vmax, and nonsaturable uptake clearance, kns, were similar in the presence and absence of DHEAS, indicating that DHEAS may change the recognition characteristics of the transporter for AZT in TR-TBT 18d-1. Thus, the increase of AZT uptake in TR-TBT 18d-1 cells in the presence of DHEAS was concluded to be because of a DHEAS-induced change in the affinity of AZT uptake system, although the transporter responsible for AZT uptake has not been identified.
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Conditionally immortalized syncytiotrophoblast cell lines as new tools for study of the Blood-Placenta Barrier.
Biological & pharmaceutical bulletin, 2004Co-Authors: Tomohide Kitano, Hisashi Iizasa, In Won Hwang, Yoko Hirose, Tomonari Morita, Tomomi Maeda, Emi NakashimaAbstract:Syncytiotrophoblasts play an essential role in restriction of drug delivery through the Blood-Placenta Barrier (BPB). Conditionally immortalized syncytiotrophoblast cell lines, TR-TBTs, were established at gestational day 18 from pregnant transgenic rats (Tg-rats) harboring the temperature-sensitive SV 40 (ts SV40) large T-antigen. TR-TBTs exhibit temperature-sensitive cell growth due to the expression of SV 40 large T-antigen, and thus the cell growth can be regulated by changing the culture temperature. TR-TBTs exhibit typical properties of syncytiotrophoblast cells, such as syncytium-like morphology, the expression of cytokeratins and hormones, and polarized expression of glucose transporter 1 (GLUT1) and GLUT3. TR-TBTs express in vivo influx and efflux transporters, such as taurine transporter (TauT), betaine/GABA transporter (BGT-1), amino acid transporter 2 (ATA2), organic anion transporting polypeptide 2 (oatp2), organic cation/carnitine transporter (OCTN2), P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP/ABCG2). Moreover, TR-TBTs exhibit taurine, GABA, and DHEA-S uptake activity via TauT, BGT-1, and oatp2, respectively. Therefore, TR-TBTs can be used for the analysis of these functions and would be a good in vitro models for investigating carrier-mediated transport functions at the BPB.
Daniele Piomelli - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological characterization of the peripheral FAAH inhibitor URB937 in female rodents: interaction with the Abcg2 transporter in the Blood‐Placenta Barrier
British journal of pharmacology, 2012Co-Authors: Guillermo Moreno-sanz, Oscar Sasso, Ana Guijarro, O Oluyemi, Rosalia Bertorelli, Angelo Reggiani, Daniele PiomelliAbstract:BACKGROUND AND PURPOSE URB937 is a peripherally restricted inhibitor of the anandamide-deactivating enzyme fatty-acid amide hydrolase (FAAH). Despite its limited access to the CNS, URB937 produces marked antinociceptive effects in rodents. URB937 is actively extruded from the CNS by the ATP-binding cassette (ABC) membrane transporter, Abcg2. Tissue Abcg2 levels are markedly different between males and females, and this transporter is known to limit the access of xenobiotics to the fetoPlacental unit in gestating female rodents. In the present study, we investigated the tissue distribution and antinociceptive properties of URB937 in female mice and rats. EXPERIMENTAL APPROACH We studied the systemic disposition of URB937 in female mice and the antinociceptive effects of this compound in models of visceral (acetic acid-induced writhing) and inflammatory nociception (carrageenan-induced hyperalgesia) in female mice and rats. Furthermore, we evaluated the interaction of URB937 with the Blood-Placenta Barrier in gestating mice and rats. KEY RESULTS Abcg2 restricted the access of URB937 to the CNS of female mice and rats. Nevertheless, URB937 produced a high degree of antinociception in female mice and rats in models of visceral and inflammatory pain. Moreover, the compound displayed a restricted access to Placental and fetal tissues in pregnant mice and rats. CONCLUSIONS AND IMPLICATIONS Peripheral FAAH blockade with URB937 reduces nociception in female mice and rats, as previously shown for males of the same species. In female mice and rats, Abcg2 limits the access of URB937, not only to the CNS, but also to the fetoPlacental unit. LINKED ARTICLES This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8
Guillermo Moreno-sanz - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological characterization of the peripheral FAAH inhibitor URB937 in female rodents: interaction with the Abcg2 transporter in the Blood‐Placenta Barrier
British journal of pharmacology, 2012Co-Authors: Guillermo Moreno-sanz, Oscar Sasso, Ana Guijarro, O Oluyemi, Rosalia Bertorelli, Angelo Reggiani, Daniele PiomelliAbstract:BACKGROUND AND PURPOSE URB937 is a peripherally restricted inhibitor of the anandamide-deactivating enzyme fatty-acid amide hydrolase (FAAH). Despite its limited access to the CNS, URB937 produces marked antinociceptive effects in rodents. URB937 is actively extruded from the CNS by the ATP-binding cassette (ABC) membrane transporter, Abcg2. Tissue Abcg2 levels are markedly different between males and females, and this transporter is known to limit the access of xenobiotics to the fetoPlacental unit in gestating female rodents. In the present study, we investigated the tissue distribution and antinociceptive properties of URB937 in female mice and rats. EXPERIMENTAL APPROACH We studied the systemic disposition of URB937 in female mice and the antinociceptive effects of this compound in models of visceral (acetic acid-induced writhing) and inflammatory nociception (carrageenan-induced hyperalgesia) in female mice and rats. Furthermore, we evaluated the interaction of URB937 with the Blood-Placenta Barrier in gestating mice and rats. KEY RESULTS Abcg2 restricted the access of URB937 to the CNS of female mice and rats. Nevertheless, URB937 produced a high degree of antinociception in female mice and rats in models of visceral and inflammatory pain. Moreover, the compound displayed a restricted access to Placental and fetal tissues in pregnant mice and rats. CONCLUSIONS AND IMPLICATIONS Peripheral FAAH blockade with URB937 reduces nociception in female mice and rats, as previously shown for males of the same species. In female mice and rats, Abcg2 limits the access of URB937, not only to the CNS, but also to the fetoPlacental unit. LINKED ARTICLES This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8
Herbert Tempfer - One of the best experts on this subject based on the ideXlab platform.
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The Blood-tendon Barrier: identification and characterisation of a novel tissue Barrier in tendon Blood vessels.
European Cells and Materials, 2016Co-Authors: Christine Lehner, R Gehwolf, Stefanie Korntner, Hannelore Bauer, Hans-christian Bauer, Andreas Traweger, Herbert TempferAbstract:Tissue Barriers function as "gate keepers" between different compartments (usually Blood and tissue) and are formed by specialised membrane-associated proteins, localising to the apicolateral plasma membrane domain of epithelial and endothelial cells. By sealing the paracellular space, the free diffusion of solutes and molecules across epithelia and endothelia is impeded. Thereby, tissue Barriers contribute to the establishment and maintenance of a distinct internal and external environment, which is crucial during organ development and allows maintenance of an organ-specific homeostatic milieu. So far, various epithelial and endothelial tissue Barriers have been described, including the Blood-brain Barrier, the Blood-retina Barrier, the Blood-testis Barrier, the Blood-Placenta Barrier, and the cerebrospinal fluid (CSF)-brain Barrier, which are vital for physiological function and any disturbance of these Barriers can result in severe organ damage or even death. Here, we describe the identification of a novel Barrier, located in the vascular bed of tendons, which we term the Blood-tendon Barrier (BTB). By using immunohistochemistry, transmission electron microscopy, and tracer studies we demonstrate the presence of a functional endothelial Barrier within tendons restricting the passage of large Blood-borne molecules into the surrounding tendon tissue. We further provide in vitro evidence that the BTB potentially contributes to the creation of a distinct internal tissue environment impacting upon the proliferation and differentiation of tendon-resident cells, effects which might be fundamental for the onset of tendon pathologies.
Moon-koo Chung - One of the best experts on this subject based on the ideXlab platform.
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TransPlacental pharmacokinetics of the new fluoroquinolone DW-116 in pregnant rats.
Toxicology letters, 2003Co-Authors: Jong-choon Kim, Chun-sik Bae, Sung-ho Kim, Hyo-in Yun, Seung-chun Park, Ho-chul Shin, Junghee Han, Moon-koo ChungAbstract:DW-116 is a newly developed fluoroquinolone antibacterial with a broad spectrum against both gram-positive and gram-negative bacteria. Recently, we have reported that DW-116 induces a significant developmental toxicity in rat. The present study was undertaken to characterize the Placental transfer and pharmacokinetics of DW-116 in Sprague-Dawley rats. Pregnant females were given a single oral dose of 500-mg [14C]DW-116/kg on gestational day 18. Maternal and fetal tissues were collected at 0.17, 0.5, 1, 2, 4, 8 and 24 h after dosing. The [14C]DW-116-derived radioactivity was rapidly distributed to the fetus and slowly eliminated from the tissue. The radioactivity in both maternal plasma and fetal tissue reached its peak within 1 h and maintained the level of radioactivity up to 16-28% of the peak level until 24 h after dosing. Radioactivity in whole fetus was higher than those in the maternal plasma and Placenta. The T(1/2)abs, T(1/2)beta, AUC, Tmax and Cmax in the maternal plasma were approximately 6 min, 13.3 h, 1620 microg h/ml, 0.5 h and 136 microg/ml, respectively. Those in the Placenta were approximately 20 min, 12.3 h, 2150 microg h/ml, 1.0 h and 172 microg/ml, respectively. Those in the whole fetus were 13 min, 12.8 h, 2549 microg h/ml, 1 h and 191 microg/ml, respectively. In the amniotic fluid of maternal uterus, the T(1/2)abs, T(1/2)beta, AUC, Tmax and Cmax were approximately 1.3 h, 9.3 h, 2508 microg h/ml, 4.4 h, and 135 microg/ ml, respectively. While DW-116 disappeared biphasically from maternal plasma, whole fetus and Placenta, it was eliminated monophasically from amniotic fluid. These results indicate that (1) total radioactivity appeared rapidly in maternal plasma and fetuses; (2) the elimination of total radioactivity is slow; and (3) DW-116 or relevant metabolites could cross the Blood-Placenta Barrier in pregnant rats.
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TransPlacental pharmacokinetics of the new fluoroquinolone DW-116 in pregnant rats.
Toxicology Letters, 2003Co-Authors: Jong-choon Kim, Chun-sik Bae, Sung-ho Kim, Hyo-in Yun, Seung-chun Park, Ho-chul Shin, Junghee Han, Moon-koo ChungAbstract:Abstract DW-116 is a newly developed fluoroquinolone antibacterial with a broad spectrum against both Gram-positive and Gram-negative bacteria. Recently, we have reported that DW-116 induces a significant developmental toxicity in rat. The present study was undertaken to characterize the Placental transfer and pharmacokinetics of DW-116 in Sprague–Dawley rats. Pregnant females were given a single oral dose of 500-mg [ 14 C]DW-116/kg on gestational day 18. Maternal and fetal tissues were collected at 0.17, 0.5, 1, 2, 4, 8 and 24 h after dosing. The [ 14 C]DW-116-derived radioactivity was rapidly distributed to the fetus and slowly eliminated from the tissue. The radioactivity in both maternal plasma and fetal tissue reached its peak within 1 h and maintained the level of radioactivity up to 16–28% of the peak level until 24 h after dosing. Radioactivity in whole fetus was higher than those in the maternal plasma and Placenta. The T 1/2, abs , T 1/2, β , AUC, T max and C max in the maternal plasma were approximately 6 min, 13.3 h, 1620 μg h/ml, 0.5 h and 136 μg/ml, respectively. Those in the Placenta were approximately 20 min, 12.3 h, 2150 μg h/ml, 1.0 h and 172 μg/ml, respectively. Those in the whole fetus were 13 min, 12.8 h, 2549 μg h/ml, 1 h and 191 μg/ml, respectively. In the amniotic fluid of maternal uterus, the T 1/2, abs , T 1/2, β , AUC, T max and C max were approximately 1.3 h, 9.3 h, 2508 μg h/ml, 4.4 h, and 135 μg/ml, respectively. While DW-116 disappeared biphasically from maternal plasma, whole fetus and Placenta, it was eliminated monophasically from amniotic fluid. These results indicate that (1) total radioactivity appeared rapidly in maternal plasma and fetuses; (2) the elimination of total radioactivity is slow; and (3) DW-116 or relevant metabolites could cross the Blood-Placenta Barrier in pregnant rats.