TY - JOUR. T1 - Bile acid efflux mediated by the rat liver canalicular bile acid transport/ecto-ATPase protein requires serine 503 phosphorylation and is regulated by tyrosine 488 phosphorylation. AU - Sippel, C. Jeffrey. AU - Fallon, Robert J.. AU - Perlmutter, David H.. PY - 1994/7/29. Y1 - 1994/7/29. N2 - Transfection of cDNA for a hepatocyte canalicular phosphoprotein, the rat liver canalicular bile acid transporter/ecto-ATPase/cell CAM 105, confers bile acid efflux and ecto-ATPase activities on heterologous cells (Sippel, C. J., Suchy, F. J., Ananthanarayanan, M., and Perlmutter D. H. (1993) J. Biol. Chem. 268, 2083-2091). Our previous studies have also indicated that there is a positive correlation between the degree of phosphorylation of this transporter and its bile acid efflux activity. In this study, we introduced site-specific mutations of amino acid residues within a protein kinase C- dependent (T502A, S503A) and a tyrosine kinase-dependent (Y488F) phosphorylation consensus sequence ...
Intrahepatic cholestasis represents 20%-40%of drug-induced injuries from which a large proportion remains unpredictable. We aimed to investigate mechanisms underlying drug-induced cholestasis and improve its early detection using human HepaRG cells and a set of 12 cholestatic drugs and six noncholestatic drugs. In this study, we analyzed bile canaliculi dynamics, Rho kinase (ROCK)/myosin light chain kinase (MLCK) pathway implication, efflux inhibition of taurocholate [a predominant bile salt export pump (BSEP) substrate], and expression of the major canalicular and basolateral bile acid transporters. We demonstrated that 12 cholestatic drugs classified on the basis of reported clinical findings caused disturbances of both bile canaliculi dynamics, characterized by either dilatation or constriction, and alteration of the ROCK/MLCK signaling pathway, whereas noncholestatic compounds, by contrast, had no effect. Cotreatment with ROCK inhibitor Y-27632 [4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide
Disruption of the murine mdr2 gene leads to the complete absence of biliary phospholipids. We tested the hypothesis that the increase in biliary phospholipid output induced by fibrates is mediated via induction of the hepatic mdr2 gene and its encoded product, the P-glycoprotein canalicular flippase. Increased levels of mdr2 mRNA were observed in the liver of mice treated with different fibrates: ciprofibrate, 660±155% (as compared with control group); clofibrate, 611±77%; bezafibrate, 410±47%; fenofibrate, 310±52%; gemfibrozil, 190±25% (P , 0.05 compared with control group). Induction of expression of the mdr gene family was specific to the mdr2 gene. Two- to three-fold increases in P-glycoprotein immunodetection were evident on the canalicular plasma-membrane domain of clofibrate- and ciprofibrate-treated mice. Biliary phospholipid output increased from 4.2±1.2 nmol/min per g of liver in the control group to 8.5±0.6, 7.1±2.9 and 5.8±2.5 in ciprofibrate-, clofibrate- and ...
Recent studies have suggested that the canalicular bile salt transport system of rat liver corresponds to a 100-kDa membrane glycoprotein. In the present study we attempted to functionally reconstitute the 100-kDa protein into artificial proteoliposomes. Canalicular membrane proteins were solubilized with octyl glucoside in the presence of asolectin phospholipids. The extracts were treated with preimmune serum or the 100-kDa protein selectively immunoprecipitated with a polyclonal antiserum. Proteins remaining in the supernatant were then incorporated into proteoliposomes by gel-filtration chromatography. Canalicular proteoliposomes containing the 100-kDa protein exhibited transstimulatable taurocholate uptake that could be inhibited by 4,4-diisothiocyanato-2,2-stilbenedisulfonic acid (DIDS). In contrast, no DIDS-sensitive transstimulatable taurocholate uptake was found in 100-kDa protein-free canalicular proteoliposomes. However, when the immunoprecipitated 100-kDa protein was dissociated ...
In this study, we have characterized the pathway of ATP7B transport from the TGN to the bile canaliculus in response to the elevation of intracellular Cu+ levels in the rat hepatoma cell line Can 10.. The Cu+-induced release of ATP7B from the TGN was found to be a rapid process that begins within 5 min of the addition of 40 µM Cu+ and is completed within 20-25 min. Treatment with bafilomycin A1 delayed the detachment of the cisterna carrying ATP7B from the TGN, demonstrating that cisterna detachment is a prerequisite to the generation of transport vesicles, as has previously been described in plants (Uemura et al., 2014). This process is pH dependent, and the rapidity of this occurrence in mammalian cells is probably why it has not been previously observed in organisms other than plants. Our studies also show that the vesicles loaded with ATP7B budding from the TGN do not contain lysosomal membrane proteins, suggesting that these are instead segregated into vesicles distinct from those ...
Gerloff, T., Meier, P. J. and Stieger, B. (1998), Taurocholate induces preferential release of phosphatidylcholine from rat liver canalicular vesicles. Liver, 18: 306-312. doi: 10.1111/j.1600-0676.1998.tb00810.x ...
The discovery of unidirectional, ATP-dependent canalicular transport systems (also termed export pumps) for bile salts, amphiphilic anionic conjugates, lipophilic cations, and phospholipids has opened new opportunities for understanding biliary phy
Stieger, Bruno; Kullak-Ublick, Gerd A (2013). Bile salt Export Pump BSEP (ABCB11): Role in liver physiology and liver disease. In: Ishikawa, T; Kim, R B; König, J. Pharmacogenomics of Human Drug Transporters: Clinical Impacts. Hoboken, NJ, USA: Wiley-Blackwell, 295-309. ...
Multiplicity for the transport of organic anions across the bile canalicular membrane was studied in vivo and in vitro using dibromosulfophthalein (DBSP), [14C]cefodizime, [3H]leukotriene C4 (LTC4) and indocyanine green (ICG) as model compounds in rats. A high concentration of DBSP in plasma reduced the biliary excretion of cefodizime and leukotriene radioactivity to about 15 and 35% of their control values, respectively, but did not affect the excretion of ICG. A high plasma concentration of ICG reduced the excretion of cefodizime to about 60% of the control value, but exerted minimal effect on the excretion of leukotriene radio-activity and DBSP. In vitro, ATP-dependent uptake of LTC4 into the canalicular membrane vesicles was reduced by DBSP, cefodizime and ICG in a dose-dependent manner, with approximate IC50 values of 0.1 microM, 10 microM, and 1 microM, respectively. The hepatic unbound concentration of DBSP sufficient to reduce the excretion of cefodizime, leukotriene radioactivity and ...
TY - JOUR. T1 - The unique polarity phenotype of hepatocytes. AU - Müsch, Anne. PY - 2014/11/1. Y1 - 2014/11/1. N2 - Hepatocytes, the main epithelial cell type of the liver, function like all epithelial cells to mediate the vectorial flow of macromolecules into and out of the organ they encompass. They do so by establishing polarized surface domains and by restricting paracellular flow via their tight junctions and cell-cell adhesion. Yet, the cell and tissue organization of hepatocytes differs profoundly from that of most other epithelia, including those of the digestive and urinary tracts, the lung or the breast. The latter form monolayered tissues in which the apical domains of individual cells align around a central continuous luminal cavity that constitutes the tubules and acini characteristic of these organs. Hepatocytes, by contrast, form capillary-sized lumina with multiple neighbors resulting in a branched, tree-like bile canaliculi network that spreads across the liver parenchyme. I ...
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Taxonomic Characterization: Male: Anterodorsal plate (AD) with a small frontal spine. In posterior portion of AD elevated ridges, arranged like an "H". Within these ridges, deep canaliculi piercing the integumental layers. Outside the ridges, slight paneling and small pores present. Posterodorsal plate with 2 elevated, longitudinal ridges, converging posteriorly but not meeting. Dorsal setae minute. Red-brown pigment is found beneath the AD near the anterior spine and beneath the OC between the corneae. All ventral plates finely porose; when focused on deeper integumental layers, a reticulation is discernible. Genitoanal plate short. Genital opening in the middle of the plate. Distance from GO to anterior margin of GA equals length of GO. Integument on base of gnathosoma pierced by canaliculi. Rostrum as long as base of gnathosoma. Integument of legs pierced by canaliculi, these especially prominent on telofermora and tibiae. Leg I stronger than following legs. The lateral claws on tarsus I are ...
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The process of differentiation of HepaRG™ into hepatocytes is long, as it takes approximately two weeks to reach the necessary confluency of cells. In addition to this, as the cells are randomly organized, bile caniculae forming in between cells are difficult to be visualized and quantified.. ...
During the summer, most people find themselves going to bed later than usual. However, this habit does have a negative toll on your body. What is staying up late? 12 am? 3 am? Everybodys body has a different perception of staying up late. Late doesnt have so much to do with the hour, rather…
What exactly is a couplet? Is that two PVCs occuring in a row? Are they more dangerous than single PVCs? What about 3 or 4 in a row? Last night, I was driving home from work and I felt a really...
The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is the major canalicular bile salt export pump in man. Mutations in this gene cause a form of progressive familial intrahepatic cholestases which are a group of inherited disorders with severe cholestatic liver disease from early infancy. [provided by RefSeq, Jul 2008 ...
A number of processes could have contributed to the lower canalicular enzyme activities in diclofenac-treated rats including: 1) redistribution of proteins from the canalicular membrane to other intracellular domains, 2) decreased protein synthesis, or 3) decreased activity as a result of adduct formation. It has been reported that several models of cholestasis are associated with redistribution of canalicular proteins and/or decreased synthesis (Barr and Hubbard, 1993; Stieger et al., 1994; Rost et al., 1999). For example, phalloidin-induced cholestasis in rats causes redistribution of ecto-ATPase, dipeptidylpeptidase IV, and a number of ATP-dependent transporter proteins as a result of disruption and internalization of canalicular membrane fragments (Rost et al., 1999). Bile duct ligation in rats has also been associated with decreased localization of dipeptidylpeptidase IV and ecto-ATPase to canalicular membranes and intracellular accumulation as a result of altered delivery of newly ...
Gene name: ATP binding cassette subfamily B, member 11 (ABCB11). Summary. ABCB11, more commonly referred to as BSEP (Bile Salt Export Pump) is a uni-directional, ATP-dependent efflux transporter that plays an important role in the elimination of bile salts from the hepatocyte into the bile canaliculi for export into the gastrointestinal tract (GIT). It is almost exclusively expressed in the liver, with much lower levels reported in the kidney. It is predominantly of relevance to hepatotoxicity, as BSEP inhibition by a drug and/or its metabolites can result in the build-up of bile salts in the liver, which can lead to cholestasis and drug-induced liver injury (DILI). Compared to other drug transporters there are only few identified drug substrates and inhibitors of BSEP; thus, its involvement in drug-drug interactions (DDI) is very limited. The relevance of in vitro BSEP inhibition as a predictor of clinical outcomes is not clearly established, but whenever cholestatic liver injury is observed in ...
Specialized transmembrane proteins recognize the substance and allow it to move across the membrane when it otherwise would not, either because the phospholipid bilayer of the membrane is impermeable to the substance moved or because the substance is moved against the direction of its concentration gradient.[7] There are two forms of active transport, primary active transport and secondary active transport. In primary active transport, the proteins involved are pumps that normally use chemical energy in the form of ATP. Secondary active transport, however, makes use of potential energy, which is usually derived through exploitation of an electrochemical gradient. The energy created from one ion moving down its electrochemical gradient is used to power the transport of another ion moving against its electrochemical gradient.[8] This involves pore-forming proteins that form channels across the cell membrane. The difference between passive transport and active transport is that the active transport ...
hypothetical protein, ABCB1LB, ATP-binding cassette, sub-family B (MDR/TAP), member 1-like B, A306_07528, ABC16, ABC member 16, MDR/TAP subfamily, AS27_06659, AS28_00614, ATP-binding cassette protein B11, ATP-binding cassette, sub-family B (MDR/TAP), member 11, ATP-binding cassette, subfamily B (MDR/TAP), member 11, ATP-binding cassette, sub-family B (MDR/TAP), member 11-like protein, ATP-binding cassette sub-family B member 11, ATP-binding cassette, sub-family B, member 11, bile salt export pump, BRIC2, BSEP, BSEP/SPGP, CB1_000638007, D623_10034923, GW7_06212, H920_16172, I79_001236, Lith1, liver bile salt export pump, M91_01875, M959_07155, MDA_GLEAN10024246, Multidrug resistance protein 1, N301_03105, N302_06788, N303_07198, N305_06591, N306_04080, N307_07545, N308_11810, N309_07944, N312_11735, N321_13718, N327_01303, N328_07355, N329_09470, N331_01374, N332_02914, N333_01536, N334_13094, N336_04014, N340_01262, N341_10800, PAL_GLEAN10025937, PFIC2, PFIC-2, PGY4, progressive familial ...
We have compared by immunocytochemistry and immunoblotting the expression and distribution of adhesion molecules participating in cell-matrix and cell-cell interactions during embryonic development and regeneration of rat liver. Fibronectin and the fibronectin receptor, integrin alpha 5 beta 1, were distributed pericellularly and expressed at a steady level during development from the 16th day of gestation and in neonate and adult liver. AGp110, a nonintegrin fibronectin receptor was first detected on the 17th day of gestation in a similar, nonpolarized distribution on parenchymal cell surfaces. At that stage of development haemopoiesis is at a peak in rat liver and fibronectin and receptors alpha 5 beta 1 and AGp110 were prominent on the surface of blood cell precursors. During the last 2 d of gestation (20th and 21st day) hepatocytes assembled around lumina. AGp110 was initially depolarized on the surface of these acinar cells but then confined to the lumen and to newly-formed bile canaliculi. ...
A novel hard transmission X-ray microscope (TXM) at the Stanford Synchrotron Radiation Light-source operating from 5 to 15 keV X-ray energy with 14 to 30 mu m(2) field of view has been used for high-resolution (30-40 nm) imaging and density quantification of mineralized tissue. TXM is uniquely suited for imaging of internal cellular structures and networks in mammalian mineralized tissues using relatively thick (50 mu m), untreated samples that preserve tissue micro-and nanostructure. To test this method we performed Zernike phase contrast and absorption contrast imaging of mouse cancellous bone prepared under different conditions of in vivo loading, fixation, and contrast agents. In addition, the three-dimensional structure was examined using tomography. Individual osteocytic lacunae were observed embedded within trabeculae in cancellous bone. Extensive canalicular networks were evident and included processes with diameters near the 30-40 nm instrument resolution that have not been reported ...
Sigma-Aldrich offers abstracts and full-text articles by [Brandy Garzel, Hui Yang, Lei Zhang, Shiew-Mei Huang, James E Polli, Hongbing Wang].
The purpose was to determine the effect on the morphine-morphine glucuronide systems of Triton X-100 instilled into the area of the hepatic canalicular membrane by segmented retrograde intrabiliary injection (40 microliters of 0.4% Triton + 31 microliters of saline) in the isolated in situ perfused livers of male Sprague-Dawley rats. In all experiments, [14C]morphine was given by segmented retrograde intrabiliary injection (40 microliters of [14C]morphine + 110 microliters of saline). The control single pass perfusate contained 15.8% [14C]morphine glucuronide (MG) and 6.2% [14C]morphine. With Triton, the major changes observed were an unusual plateau-like pattern of egress of the [14C]MG into the perfusate and a profound decrease in the [14C]MG excretion into bile. In controls, 45 mg of unlabeled morphine sulfate intraportally 5 min before the [14C]morphine reduced the perfusate [14C]MG and increased [14C]morphine as expected by isotope dilution. Also, [14C]MG recovery in bile was accordingly ...
annotations (the reliablity of the annotated protein expression using immunohistochemically (IH) stained on human tissues, the reliablity of the annotated protein expression in immunofluorescently (IF) stained human cell lines, tissue specificity (the distribution of antibody staining or protein expression in human cell types), cell line specificity (the distribution of RNA abundance in cell lines) and subcellular location (based on immunofluorescent staining of cell lines ...
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Yang C; Pinart M; Kolsteren P; Van Camp J; De Cock N; Nimptsch K; Pischon T; Laird L; Perozzi P; Canali R; Hoge A; Stelmach-Mardas M; Ove Dragsted L; Palombi SM; Dobre I; Bouwman J; Clarys P; Minervini F; De Angelis M; Gobbetti M; Tafforeau J; Coltell O; Corella D; De Ruyck H; Walton J; Kehoe L; Matthys C; De Baets B; De Tré G; Bronselaer A; Rivellese A; Giacco R; Lombardo R; De Clercq S; Hulstaert N; Lachat C (2017) ...
Yang C; Pinart M; Kolsteren P; Van Camp J; De Cock N; Nimptsch K; Pischon T; Laird L; Perozzi P; Canali R; Hoge A; Stelmach-Mardas M; Ove Dragsted L; Palombi SM; Dobre I; Bouwman J; Clarys P; Minervini F; De Angelis M; Gobbetti M; Tafforeau J; Coltell O; Corella D; De Ruyck H; Walton J; Kehoe L; Matthys C; De Baets B; De Tré G; Bronselaer A; Rivellese A; Giacco R; Lombardo R; De Clercq S; Hulstaert N; Lachat C (2017) ...
Purpose. To investigate the microstructure of the lacrimal canaliculus and the characteristics of lacrimal canalicular diseases by 80-MHz ultrasound biomicroscopy (UBM).. Methods. This study included 33 participants: 20 normal subjects (40 eyes), 2 patients with chronic lacrimal canaliculitis (4 eyes), 10 patients with chronic dacryocystitis (16 eyes), and 1 patient with lacrimal punctum atresia (2 eyes). All participants underwent 80-MHz UBM; disease-specific features were noted.. Results. On 80-MHz UBM of the lacrimal canaliculi (vertical section) in normal subjects, low echo of the lacrimal canalicular lumen and high echo of the lacrimal canalicular wall were observed. The uniform low echo near the wall was the mucosal epithelium. The outermost layer of medium-to-high echo was the subepithelial elastic fibrous layer. In the horizontal section, the lumen was continuous. Two linear high echoes parallel to the canalicular wall could be observed at the center of the lacrimal canaliculus, which ...
The Lith1 region on Chromosome (Chr) 2 contains a gene that markedly affects the prevalence of cholesterol gallstones in inbred mice. We report the high-resolution genetic and radiation hybrid maps of the chromosomal region surrounding Lith1, using three resources: a DNA panel from 188 progeny from two reciprocal backcrosses between C57BL/6 and Mus spretus inbred strains; 423 progeny of an N4 generation from backcrossing the susceptible C57L/J alleles at Lith1 into the resistant AKR/J strain; and the newly developed hamster-mouse T31 radiation hybrid panel. We mapped 17 microsatellite markers in the D2Mit182 to D2Mit14 region and two candidate genes for Lith1, the canalicular bile salt export pump (Bsep) also known as sister of P-glycoprotein (Spgp) and the low-density-lipoprotein-receptor-related gene megalin (Gp330). Both genetic maps were in agreement and ordered the microsatellite markers into a 10.4 +/- 1.5 cM region. The high-resolution physical map revealed ordering of microsatellite
The bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepatocytes. Its physiological role is to expel bile salts into the canaliculi from where they drain into the bile duct. Inhibition of this transporter may lead to intrahepatic cholestasis. Predictive computational models of BSEP inhibition may allow for fast identification of potentially harmful compounds in large databases. This article presents a predictive in silico model based on physicochemical descriptors that is able to flag compounds as potential BSEP inhibitors. This model was built using a training set of 670 compounds with available BSEP inhibition potencies. It successfully predicted BSEP inhibition for two independent test sets and was in a further step used for a virtual screening experiment. After in vitro testing of selected candidates, a marketed drug, bromocriptin, was identified for the first time as BSEP inhibitor. This demonstrates the usefulness of the model to identify new BSEP ...
FUNCTION: The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions in the canalicular surface of the hepatocyte and in biliary transport, and appears to contribute to drug resistance in mammalian cells. Several different mutations in the human gene have been observed in patients with Dubin-Johnson syndrome (DJS), an autosomal recessive disorder characterized by conjugated hyperbilirubinemia. Alternative splice variants have been observed for this gene; however, they have not been fully described. [provided by RefSeq, Jul 2008 ...
A light-and electron-microscopic study of pig hepatocytes from late prenatal to early neonatal animals shows changes which reflect an increasing rate of synthetic activity. The granular endoplasmic reticulum (ER) in the prenatal pig hepatocyte is situated along the periphery of the cytoplasm and in the region immediately surrounding the nucleus. Mitochondria are most abundant in the area adjacent to the nucleus, while the Golgi complex is generally located in the region of the bile canaliculus. The remaining portion of the hepatocyte is occupied with glycogen. A few hours after birth the hepatocyte increases about twofold in size with the nucleus shifting from a peripheral to a more centrally located position. The glycogen decreases quickly coincident with a rapid increase in the amount of granular ER and the dispersion of the mitochondria throughout the cell. The Golgi complex becomes distended and numerous vesicles appear in its immediate vicinity containing a moderately dense material. ...
Cell-derived membrane vesicles (CMVs) are endogenous carriers transporting proteins and nucleic acids between cells. They appear to play an important role in many disease processes, most notably inflammation and cancer, where their efficient functional delivery of biological cargo seems to contribute to the disease progress. CMVs encompass a variety of submicron vesicular structures that include exosomes and shedding vesicles. The lipids, proteins, mRNA and microRNA (miRNA) delivered by these vesicles change the phenotype of the receiving cells. CMVs have created excitement in the drug delivery field, because they appear to have multiple advantages over current artificial drug delivery systems. Two approaches to exploit CMVs for delivery of exogenous therapeutic cargoes in vivo are currently considered. One approach is based on engineering of natural CMVs in order to target certain cell types using CMVs loaded with therapeutic compounds. In the second approach, essential characteristics of CMVs are
The IUPHAR/BPS Guide to Pharmacology. trandolaprilat ligand page. Quantitative data and detailed annnotation of the targets of licensed and experimental drugs.
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Uchiumi T., Hinoshita E., Haga S., Nakamura T., Tanaka T., Toh S., Furukawa M., Kawabe T., Wada M., Kagotani K., Okumura K., Kohno K., Akiyama S., Kuwano M.. The human multidrug resistance protein (MRP) gene encodes a membrane protein involved in the ATP-dependent transport of hydrophobic compounds. We previously isolated a canalicular multispecific organic anion transporter, cMOAT1/MRP2, that belongs to the ATP binding cassette (ABC) superfamily, which is specifically expressed in liver, and cMOAT1/MRP2 is responsible for the defects in hyperbilirubinemia II/Dubin-Johnson syndrome. In this study, we isolated a new cDNA of the ABC superfamily designated cMOAT2/MRP3 that is homologous to human MRP1 and cMOAT1/MRP2: cMOAT2/MRP3 is 56% identical to MRP1 and 45% identical to cMOAT1/MRP2, respectively. Fluorescence in situ hybridization demonstrated the chromosomal locus of this gene on chromosome 17q22. The human cMOAT2 cDNA hybridized to a 6.5-kb mRNA that was mainly expressed in liver and to a ...
TY - JOUR. T1 - X-linked cholestasis in mouse due to mutations of the P4-ATPase ATP11C. AU - Siggs, Owen M.. AU - Schnabl, Bernd. AU - Webb, Bill. AU - Beutler, Bruce. PY - 2011/5/10. Y1 - 2011/5/10. N2 - Transporters at the hepatic canalicular membrane are essential for the formation of bile and the prevention of cholestatic liver disease. One such example is ATP8B1, a P4-type ATPase disrupted in three inherited forms of intrahepatic cholestasis. Mutation of the X-linked mouse gene Atp11c, which encodes a paralogous P4-type ATPase, precludes B-cell development in the adult bone marrow, but also causes hyperbilirubinemia. Here we explore this hyperbilirubinemia in two independent Atp11c mutant mouse lines, and find that it originates from an effect on nonhematopoietic cells. Liver function tests and histology revealed only minor pathology, although cholic acid was elevated in the serum of mutant mice, and became toxic to mutant mice when given as a dietary supplement. The majority of homozygous ...
Implant devices, systems and methods for insertion into a punctum of a patient optionally comprises a drug core and a sheath body disposed over the drug core. The drug core includes a therapeutic agent deliverable into the eye, and the sheath defines at least one exposed surface of the drug core. The exposed surface(s) of the drug core may contact a tear or tear film fluid and release the therapeutic agent at therapeutic levels over a sustained period when the implant is implanted for use. The implant may include a retention element to retain the drug core and sheath body near the punctum, optionally comprising a shape memory alloy that can resiliently expand. An occlusive element may be attached to the retention element to at least partially occlude tear flow through the canalicular lumen.
Membrane transport proteins are known to influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. At the onset of this thesis work, only a few structure-activity models, in general describing P-glycoprotein (Pgp/ABCB1) interactions, were developed using small datasets with little structural diversity. In this thesis, drug-transport protein interactions were explored using large, diverse datasets representing the chemical space of orally administered registered drugs. Focus was set on the ATP-binding cassette (ABC) transport proteins expressed in the canalicular membrane of human hepatocytes.. The inhibition of the ABC transport proteins multidrug-resistance associated protein 2 (MRP2/ABCC2) and bile salt export pump (BSEP/ABCB11) was experimentally investigated using membrane vesicles from cells overexpressing the investigated proteins and sandwich cultured human hepatocytes (SCHH). Several previously unknown inhibitors were identified for both of the proteins ...
Canali Milano charcoal birdseye wool suit 52/42R jacket, 36x30 pants Top line of Canali, full canvas construction, retailed about $2k Fratelli Tallia...
Here is a new paper on dinosaur bone histology, from this weeks Nature: Rensberger, J.M. & M. Watabe. 2000. Fine of bone in dinosaurs, birds, and mammals. Nature 406: 619-621. Unlike most papers so far on bone histology, this one concentrates on the fine-scale structures: in particular, the canaliculi and the college fibre bundles. The looked at a variety of modern mammal and bird bones, as well as previously published material on squamates and amphibians. Among fossils, they examined _Gallimimus_ and a Lancian ornithomimid, a Nemegt hadrosaur, _Protoceratops_, _Triceratops_, and previously published prosauropod material. In all non-dinosaurian taxa the canaliculi are radially oriented and the college bundles highly organized: this is almost certainly the primitive condition for tetrapods. In ornithomimids and birds the canaliculi are randomly oriented and college bundles are irregularly organized. Lamellae in the primary osteons of ornithischians and prosauropods are similar to those of the ...
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Hello everybody! I have a question concerning foreign names, to be more exact Russian names, because I translate from Russian. There are first names in Russian like Timofey, Alexey, Andrey (ey is read as a in the words fate, late etc., and not as ey in kidney, Sydney etc.). Accordingly, last names are formed by adding suffixes in Russian, on doing which we obtain, in direct transliteration, Alexeev, Timofeev, Andreev. It does not seem to be readable in English, because,
prendi con le pinza, seriamente, ogni suggerimento che ricevi qui. Noi non sappiamo che pasticci hanno combinato i developers di papublablabla sopra ad una gentoo liscia, per cui potremmo benissimo darti in buona fede dei consigli molto sbagliati. A tal proposito forse sarebbe stato più produttivo rivolgerti ai canali di supporto propri di quella particolare distribuzione ...
TY - JOUR. T1 - Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome. AU - Wada, Morimasa. AU - Toh, Satoshi. AU - Taniguchi, Ken. AU - Nakamura, Takanori. AU - Uchiumi, Takeshi. AU - Kohno, Kimitoshi. AU - Yoshida, Ichiro. AU - Kimura, Akihiko. AU - Sakisaka, Shotaro. AU - Adachi, Yukihiko. AU - Kuwano, Michihiko. PY - 1998/2. Y1 - 1998/2. N2 - Members of the ATP-binding cassette (ABC) transporter superfamily are mutated to cause diseases that include cystic fibrosis, hyperinsulinemia, adrenoleukodystrophy, Stargardt disease and multidrug resistance. We recently isolated a novel human member of ABC transporter superfamily as the candidate transporter for the glucuronide and glutathione-conjugated antitumor agents, and found it highly homologous to the rat cmoat gene. Consistent with recent findings of defects in the homologous cmoat gene in two rat models of hyperbilirubinemia ...
TY - JOUR. T1 - Expression and subcellular localization of aquaporin water channels in the polarized hepatocyte cell line, WIF-B. AU - Gradilone, Sergio A.. AU - Tietz, Pamela S.. AU - Splinter, Patrick L.. AU - Marinelli, Raúl A.. AU - LaRusso, Nicholas F.. PY - 2005/8/18. Y1 - 2005/8/18. N2 - Background: Recent data suggest that canalicular bile secretion involves selective expression and coordinated regulation of aquaporins (AQPs), a family of water channels proteins. In order to further characterize the role of AQPs in this process, an in vitro cell system with retained polarity and expression of AQPs and relevant solute transporters involved in bile formation is highly desirable. The WIF-B cell line is a highly differentiated and polarized rat hepatoma/human fibroblast hybrid, which forms abundant bile canalicular structures. This cell line has been reported to be a good in vitro model for studying hepatocyte polarity. Results: Using RT-PCR, immunoblotting and confocal immunofluorescence, ...
We have previously shown that the multidrug resistance protein (MRP) mediates the ATP-dependent membrane transport of the endogenous glutathione conjugate leukotriene C4 (LTC4) and of structurally related anionic conjugates of lipophilic compounds [Jedlitschky, Leier, Buchholz, Center and Keppler (1994) Cancer Res. 54, 4833-4836; Leier, Jedlitschky, Buchholz, Cole, Deeley and Keppler (1994) J. Biol. Chem. 269, 27807-27810]. We demonstrate in the present study that MRP also mediates the ATP-dependent transport of GSSG, as shown in membrane vesicles from human leukaemia cells overexpressing MRP (HL60/ADR cells) or HeLa cells transfected with an MRP expression vector (HeLa T5 cells) in comparison with the respective parental or control cells. The Km value for ATP-dependent transport of GSSG was 93±26 μM (mean value±S.D., n = 5) in membrane vesicles from HeLa T5 cells. GSH, at a concentration of 100 μM, was not a substrate for any significant ATP-dependent MRP-mediated transport. The transport ...
By screening databases of human expressed sequence tags, we have identified three new homologues of MRP1, the gene encoding the multidrug resistance-associated protein, and cMOAT (or MRP2), the canalicular multispecific organic anion transporter gene. We call these new genes MRP3, MRP4, and MRP5. MRP3, like cMOAT, is mainly expressed in the liver. MRP4 is expressed only at very low levels in a few tissues, and MRP5, like MRP1, is expressed in almost every tissue tested. To assess a possible role of these new MRP homologues in multidrug or cisplatin resistance, a large set of resistant cell lines was examined for the (over)expression of MRP1, cMOAT, MRP3, MRP4, and MRP5. We find that even in cells selected for a low level of resistance, several MRP-related genes can be up-regulated simultaneously. However, MRP4 is not overexpressed in any of the cell lines we analyzed; MRP3 and MRP5 are only overexpressed in a few cell lines, and the RNA levels do not seem to correlate with resistance to either ...