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1.
J Control Release ; 216: 93-102, 2015 Oct 28.
Article in English | MEDLINE | ID: mdl-26278512

ABSTRACT

Novel antitumour drugs, such as cationic tyrosine kinase inhibitors, are useful in many types of cancer but not in others, such as cholangiocarcinoma (CCA), where their uptake through specific membrane transporters, such as OCT1, is very poor. Here we have investigated the usefulness of targeting cytostatic bile acid derivatives to enhance the delivery of chemotherapy to tumours expressing the bile acid transporter ASBT and whether this is the case for CCA. The analysis of paired samples of CCA and adjacent non-tumour tissue collected from human (n=15) and rat (n=29) CCA revealed that ASBT expression was preserved. Moreover, ASBT was expressed, although at different levels, in human and rat CCA cell lines. Both cells in vitro and rat tumours in vivo were able to carry out efficient uptake of bile acid derivatives. Using Bamet-UD2 (cisplatin-ursodeoxycholate conjugate) as a model ASBT-targeted drug, in vitro and in vivo antiproliferative activity was evaluated. ASBT expression enhanced the sensitivity to Bamet-UD2, but not to cisplatin, in vitro. In nude mice, Bamet-UD2 (more than cisplatin) inhibited the growth of human colon adenocarcinoma tumours with induced stable expression of ASBT. As compared with cisplatin, administration of Bamet-UD2 to rats with CCA resulted in an efficient liver and tumour uptake but low exposure of extrahepatic tissues to the drug. Consequently, signs of liver/renal toxicity were absent in animals treated with Bamet-UD2. In conclusion, endogenous or induced ASBT expression may be useful in pharmacological strategies to treat enterohepatic tumours based on the use of cytostatic bile acid derivatives.


Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Bile Duct Neoplasms/drug therapy , Cholangiocarcinoma/drug therapy , Organic Anion Transporters, Sodium-Dependent/metabolism , Symporters/metabolism , Aged , Aged, 80 and over , Animals , Cell Line, Tumor , Cell Proliferation , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Drug Delivery Systems , Female , Humans , Male , Mice , Mice, Nude , Middle Aged , Organic Anion Transporters, Sodium-Dependent/drug effects , Organoplatinum Compounds , Rats , Rats, Wistar , Symporters/drug effects , Ursodeoxycholic Acid/chemistry
2.
Bioorg Med Chem ; 23(5): 976-84, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25650312

ABSTRACT

Sodium taurocholate cotransporting polypeptide (NTCP) is a multiple transmembrane transporter predominantly expressed in the liver, functioning as a functional receptor for HBV. Through our continuous efforts to identify NTCP as a novel HBV target, we designed and synthesized a series of new compounds based on the structure of our previous compound NT-5. Molecular docking and MD simulation validated that a new compound named NTI-007 can tightly bind to NTCP, whose efficacy was also measured in vitro virological examination and cytotoxicity studies. Furthermore, autophagy was observed in NTI-007 incubated HepG2.2.15 cells, and results of q-PCR and Western blotting revealed that NTI-007 induced autophagy through NTCP-APOA1-HBx-Beclin1-mediated pathway. Taken together, considering crucial role of NTCP in HBV infection, NTCP-mediated autophagic pathway may provide a promising strategy of HBV therapy and given efficacy of NTI-007 triggering autophagy. Our study suggests pre-clinical potential of this compound as a novel anti-HBV drug candidate.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/therapeutic use , Apolipoproteins B/drug effects , Apoptosis Regulatory Proteins/drug effects , Hepatitis B/drug therapy , Membrane Proteins/drug effects , Organic Anion Transporters, Sodium-Dependent/drug effects , Symporters/drug effects , Trans-Activators/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Autophagy/drug effects , Beclin-1 , Cell Line, Tumor , Humans , Models, Molecular , Viral Regulatory and Accessory Proteins
3.
Am J Physiol Gastrointest Liver Physiol ; 308(3): G217-22, 2015 Feb 01.
Article in English | MEDLINE | ID: mdl-25477376

ABSTRACT

Indomethacin is a powerful analgesic nonsteroidal anti-inflammatory drug (NSAID), but is limited in use by its primary side effect to cause gastrointestinal bleeding and serious injury. One factor important for exacerbating NSAID injury is the presence of bile acids, which may interact with indomethacin to form toxic mixed micelles in the gut. The development of a safer gastrointestinal formulation of indomethacin that is chemically complexed with phosphatidylcholine (PC-indomethacin) may offer an improved therapeutic agent, particularly in the presence of bile acid, but its potential protective mechanism is incompletely understood. Intestinal epithelial cells (IEC-6) were tested for injury with indomethacin (alone and plus various bile acids) compared with PC-indomethacin (alone and plus bile acids). To explore a role for bile acid uptake into cells as a requirement for NSAID injury, studies were performed using Madin-Darby canine kidney cells transfected with the apical sodium-dependent bile acid transporter (ASBT). Indomethacin, but not PC-indomethacin, was directly and dose-dependently injurious to IEC-6 cells. Similarly, the combination of any bile acid plus indomethacin, but not PC-indomethacin, induced cell injury. The expression of ASBT had a modest effect on the acute cytotoxicity of indomethacin in the presence of some conjugated bile acids. Complexing PC with indomethacin protected against the acute intestinal epithelial injury caused by indomethacin regardless of the presence of bile acids. The presence of luminal bile acid, but not its carrier-mediated uptake into the enterocyte, is required for acute indomethacin-induced cell injury. It is likely that initial cell damage induced by indomethacin occurs at or near the cell membrane, an effect exacerbated by bile acids and attenuated by PC.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Bile Acids and Salts/toxicity , Gastrointestinal Hemorrhage/drug therapy , Indomethacin/toxicity , Phosphatidylcholines/pharmacology , Animals , Cell Membrane/drug effects , Gastrointestinal Agents/pharmacology , Gastrointestinal Hemorrhage/chemically induced , Mice , Organic Anion Transporters, Sodium-Dependent/drug effects , Symporters/drug effects
4.
J Pharmacol Exp Ther ; 350(1): 130-43, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24769543

ABSTRACT

Treatment of pulmonary arterial hypertension with the endothelin receptor antagonist bosentan has been associated with transient increases in liver transaminases. Mechanistically, bosentan inhibits the bile salt export pump (BSEP) leading to an intrahepatic accumulation of cytotoxic bile salts, which eventually results in hepatocellular damage. BSEP inhibition by bosentan is amplified by its accumulation in the liver as bosentan is a substrate of organic anion-transporting polypeptide (OATP) transport proteins. The novel endothelin receptor antagonist macitentan shows a superior liver safety profile. Introduction of the less acidic sulfamide moiety and increased lipophilicity yield a hepatic disposition profile different from other endothelin receptor antagonists. Passive diffusion rather than OATP-mediated uptake is the driving force for macitentan uptake into the liver. Interaction with the sodium taurocholate cotransporting polypeptide and BSEP transport proteins involved in hepatic bile salt homeostasis is therefore limited due to the low intrahepatic drug concentrations. Evidence for this conclusion is provided by in vitro experiments in drug transporter-expressing cell lines, acute and long-term studies in rats and dogs, absence of plasma bile salt changes in healthy human volunteers after multiple dosing, and finally the liver safety profile of macitentan in the completed phase III morbidity/mortality SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) trial.


Subject(s)
ATP-Binding Cassette Transporters/drug effects , Bile Acids and Salts/blood , Liver/metabolism , Organic Anion Transporters, Sodium-Dependent/drug effects , Pyrimidines/pharmacokinetics , Pyrimidines/toxicity , Sulfonamides/pharmacokinetics , Sulfonamides/toxicity , Symporters/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 11 , Animals , Bosentan , Cell Line , Cricetinae , Dogs , Dose-Response Relationship, Drug , Endothelin Receptor Antagonists , Hepatocytes , Humans , Male , Organic Anion Transporters/drug effects , Pyrimidines/adverse effects , Rats , Sulfonamides/adverse effects
5.
Toxicol Appl Pharmacol ; 277(2): 138-45, 2014 Jun 01.
Article in English | MEDLINE | ID: mdl-24657338

ABSTRACT

Antibiotic treatments have been used to modulate intestinal bacteria and investigate the role of intestinal bacteria on bile acid (BA) homeostasis. However, knowledge on which intestinal bacteria and bile acids are modified by antibiotics is limited. In the present study, mice were administered various antibiotics, 47 of the most abundant bacterial species in intestine, as well as individual BAs in plasma, liver, and intestine were quantified. Compared to the two antibiotic combinations (vancomycin+imipenem and cephalothin+neomycin), the three single antibiotics (metronidazole, ciprofloxacin and aztreonam) have less effect on intestinal bacterial profiles, and thus on host BA profiles and mRNA expression of genes that are important for BA homeostasis. The two antibiotic combinations decreased the ratio of Firmicutes to Bacteroidetes in intestine, as well as most secondary BAs in serum, liver and intestine. Additionally, the two antibiotic combinations significantly increased mRNA of the hepatic BA uptake transporters (Ntcp and Oatp1b2) and canalicular BA efflux transporters (Bsep and Mrp2), but decreased mRNA of the hepatic BA synthetic enzyme Cyp8b1, suggesting an elevated enterohepatic circulation of BAs. Interestingly, the two antibiotic combinations tended to have opposite effect on the mRNAs of most intestinal genes, which tended to be inhibited by vancomycin+imipenem but stimulated by cephalothin+neomycin. To conclude, the present study clearly shows that various antibiotics have distinct effects on modulating intestinal bacteria and host BA metabolism.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bile Acids and Salts/metabolism , Intestines/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 11 , ATP-Binding Cassette Transporters/drug effects , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Animals , Bacteria/classification , Bacteria/growth & development , Bile Acids and Salts/blood , Drug Therapy, Combination , Enterohepatic Circulation , Gene Expression Regulation , Intestinal Mucosa/metabolism , Intestines/microbiology , Liver/drug effects , Liver/metabolism , Liver-Specific Organic Anion Transporter 1 , Male , Mice , Mice, Inbred C57BL , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/drug effects , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Organic Anion Transporters, Sodium-Dependent/drug effects , Organic Anion Transporters, Sodium-Dependent/genetics , Organic Anion Transporters, Sodium-Dependent/metabolism , Organic Anion Transporters, Sodium-Independent/drug effects , Organic Anion Transporters, Sodium-Independent/genetics , Organic Anion Transporters, Sodium-Independent/metabolism , RNA, Messenger/metabolism , Steroid 12-alpha-Hydroxylase/genetics , Steroid 12-alpha-Hydroxylase/metabolism , Symporters/drug effects , Symporters/genetics , Symporters/metabolism
6.
Pflugers Arch ; 464(4): 367-74, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22875277

ABSTRACT

2-Oxoglutarate or α-ketoglutarate (αKG) is a substrate of HIF prolyl hydroxylases 1-3 that decrease cellular levels of the hypoxia-inducible factor 1α (HIF-1α) in the presence of oxygen. αKG analogs are applied to stabilize HIF-1α even in the presence of oxygen and thus provide a novel therapeutic option in treating kidney diseases. In the kidneys, the organic anion transporters 1 and 3 (OAT1 and OAT3, respectively) in cooperation with the sodium-dependent dicarboxylate transporter 3 (NaDC3) and the OAT4 might be responsible for the uptake of αKG analogs into and the efflux out of the tubular cells. Using the radiolabelled substrates p-aminohippurate (PAH, OAT1), estrone-3-sulfate (ES; OAT3, OAT4), and succinate (NaDC3), N-oxalylglycine (NOG), dimethyloxalyl glycine (DMOG), 2,4-diethylpyridine dicarboxylate (2,4-DPD), and pyridine-2,4-dicarboxylic acid (PDCA) were tested in cis-inhibition and trans-stimulation experiments. None of these αKG analogs interacted with NaDC3. 2,4-DPD and PDCA inhibited ES uptake by OAT3 moderately. NOG, 2,4-DPD and PDCA, but not DMOG, inhibited PAH uptake by OAT1 significantly. trans-Stimulation experiments and experiments demonstrating stabilization of HIF-1α revealed that NOG and PDCA, but not 2,4-DPD, are translocated by OAT1. All compounds trans-stimulated ES uptake by OAT4, but only PDCA stabilized HIF-1α. The data suggest that OAT1 is involved in the uptake of NOG and PDCA across the basolateral membrane of proximal tubule cells, whereas OAT4 may release these compounds into the primary urine.


Subject(s)
Dioxygenases/antagonists & inhibitors , Ketoglutaric Acids/metabolism , Organic Anion Transport Protein 1/metabolism , Organic Anion Transporters/metabolism , Procollagen-Proline Dioxygenase/antagonists & inhibitors , Amino Acids, Dicarboxylic/metabolism , Biological Transport, Active , Estrone/analogs & derivatives , Estrone/metabolism , HEK293 Cells , Humans , Hypoxia-Inducible Factor 1/metabolism , Organic Anion Transporters/drug effects , Organic Anion Transporters, Sodium-Dependent/drug effects , Organic Anion Transporters, Sodium-Dependent/metabolism , Pyridines/metabolism , Succinic Acid/metabolism , Symporters/drug effects , Symporters/metabolism , p-Aminohippuric Acid/metabolism
7.
Am J Physiol Gastrointest Liver Physiol ; 298(5): G675-82, 2010 May.
Article in English | MEDLINE | ID: mdl-20075140

ABSTRACT

Previous studies have demonstrated that apical Na-bile acid cotransport (ASBT) is inhibited during chronic ileitis by both a decrease in the affinity as well as a decrease in the number of cotransporters. Methylprednisolone (MP), a commonly used treatment for inflammatory bowel disease (IBD, e.g., Crohn's disease), has been shown to reverse the inhibition of several other Na-solute cotransporters during chronic enteritis. However, the effect of MP on ASBT in the chronically inflamed ileum is not known. MP stimulated ASBT in villus cells from the normal rabbit ileum by increasing the cotransporter expression without a change in the affinity of the cotransporter for bile acid. Western blot studies demonstrated an increase in cotransporter expression. MP reversed the inhibition of ASBT in villus cells from the chronically inflamed ileum. Kinetic studies demonstrated that the mechanism of MP-mediated reversal of ASBT inhibition was secondary to a restoration of both affinity as well as cotransporter numbers. Western blot analysis demonstrated restoration of cotransporter numbers after MP treatment of rabbits with chronic ileitis. Thus MP stimulates ASBT in the normal ileum by increasing cotransporter numbers. MP reverses the inhibition of ASBT during chronic ileitis. However, MP restores the diminished affinity as well as cotransporter expression levels during chronic ileitis. Thus MP differentially regulates ASBT in the normal and in the chronically inflamed ileum.


Subject(s)
Bile Acids and Salts/metabolism , Glucocorticoids/pharmacology , Ileitis/metabolism , Ileum/metabolism , Methylprednisolone/pharmacology , Organic Anion Transporters, Sodium-Dependent/metabolism , Symporters/metabolism , Animals , Ileum/drug effects , Kinetics , Microvilli/drug effects , Microvilli/metabolism , Organic Anion Transporters, Sodium-Dependent/drug effects , Rabbits , Symporters/drug effects
8.
Biochemistry ; 47(12): 3606-14, 2008 Mar 25.
Article in English | MEDLINE | ID: mdl-18311924

ABSTRACT

We report the involvement of transmembrane domain 4 (TM4) of hASBT in forming the putative translocation pathway, using cysteine-scanning mutagenesis in conjunction with solvent-accessibility studies using the membrane-impermeant, sulfhydryl-specific methanethiosulfonate reagents. We individually mutated each of the 21 amino acids in TM4 to cysteine on a fully functional, MTS-resistant C270A-hASBT template. The single-cysteine mutants were expressed in COS-1 cells, and their cell surface expression levels, transport activities [uptake of the prototypical hASBT substrate taurocholic acid (TCA)], and sensitivities to MTS exposure were determined. Only P161 lacked cell-surface expression. Overall, cysteine replacement was tolerated at charged and polar residues, except for mutants I160C, Y162C, I165C, and G179C (

Subject(s)
Organic Anion Transporters, Sodium-Dependent/chemistry , Symporters/chemistry , Amino Acid Sequence , Animals , COS Cells , Chlorocebus aethiops , Computational Biology , Cysteine/chemistry , Cytosol/metabolism , Humans , Mesylates/chemistry , Mesylates/pharmacology , Models, Molecular , Molecular Sequence Data , Organic Anion Transporters, Sodium-Dependent/drug effects , Organic Anion Transporters, Sodium-Dependent/genetics , Point Mutation , Protein Structure, Secondary , Protein Structure, Tertiary , Sequence Alignment , Symporters/drug effects , Symporters/genetics
9.
Mol Pharm ; 3(1): 70-7, 2006.
Article in English | MEDLINE | ID: mdl-16686371

ABSTRACT

Ursodeoxycholate (UDCA) is widely used for the treatment of cholestatic liver disease. After oral administration, UDCA is absorbed, taken up efficiently by hepatocytes, and conjugated mainly with glycine to form glycoursodeoxycholate (GUDC) or partly with taurine to form tauroursodeoxycholate (TUDC), which undergo enterohepatic circulation. In this study, to check whether three basolateral transporters--Na(+)-taurocholate cotransporting polypeptide (NTCP, SLC10A1), organic anion transporting polypeptide (OATP) 1B1 (OATP-C), and OATP1B3 (OATP8)-mediate uptake of UDCA, GUDC, and TUDC by human hepatocytes, we investigated their transport properties using transporter-expressing HEK293 cells and human cryopreserved hepatocytes. TUDC and GUDC could be taken up via human NTCP, OATP1B1, and OATP1B3, whereas UDCA could be transported significantly by NTCP, but not OATP1B1 and OATP1B3 in our expression systems. We observed a time-dependent and saturable uptake of UDCA and its conjugates by human cryopreserved hepatocytes, and more than half of the overall uptake involved a saturable component. Kinetic analyses revealed that the contribution of Na(+)-dependent and -independent pathways to the uptake of UDCA or TUDC was very similar, while the Na(+)-independent uptake of GUDC was predominant. These results suggest that UDCA and its conjugates are taken up by both multiple saturable transport systems and nonsaturable transport in human liver with different contributions. These results provide an explanation for the efficient hepatic clearance of UDCA and its conjugates in patients receiving UDCA therapy.


Subject(s)
Hepatocytes/metabolism , Liver-Specific Organic Anion Transporter 1/physiology , Organic Anion Transporters, Sodium-Dependent/physiology , Organic Anion Transporters, Sodium-Independent/physiology , Symporters/physiology , Ursodeoxycholic Acid/pharmacokinetics , Cell Line , Hepatocytes/drug effects , Humans , Liver-Specific Organic Anion Transporter 1/drug effects , Organic Anion Transporters, Sodium-Dependent/drug effects , Organic Anion Transporters, Sodium-Independent/drug effects , Solute Carrier Organic Anion Transporter Family Member 1B3 , Structure-Activity Relationship , Symporters/drug effects , Taurochenodeoxycholic Acid/pharmacokinetics , Taurocholic Acid/pharmacokinetics , Ursodeoxycholic Acid/analogs & derivatives
10.
J Neurochem ; 97(1): 162-73, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16524379

ABSTRACT

Na+-coupled carboxylate transporters (NaCs) mediate the uptake of tricarboxylic acid cycle intermediates in mammalian tissues. Of these transporters, NaC3 (formerly known as Na+-coupled dicarboxylate transporter 3, NaDC3/SDCT2) and NaC2 (formerly known as Na+-coupled citrate transporter, NaCT) have been shown to be expressed in brain. There is, however, little information available on the precise distribution and function of both transporters in the CNS. In the present study, we investigated the functional characteristics of Na+-dependent succinate and citrate transport in primary cultures of astrocytes and neurons from rat cerebral cortex. Uptake of succinate was Na+ dependent, Li+ sensitive and saturable with a Michaelis constant (Kt) value of 28.4 microM in rat astrocytes. Na+ activation kinetics revealed that the Na+ to succinate stoichiometry was 3:1 and the concentration of Na+ necessary for half-maximal transport was 53 mM. Although uptake of citrate in astrocytes was also Na+ dependent and saturable, its Kt value was significantly higher (approximately 1.2 mM) than that of succinate. Unlabeled succinate (2 mM) inhibited Na+-dependent [14C]succinate (18 microM) and [14C]citrate (4.5 microM) transport completely, whereas unlabeled citrate inhibited Na+-dependent [14C]succinate uptake more weakly. Interestingly, N-acetyl-L-aspartate, which is the second most abundant amino acid in the nervous system, also completely inhibited Na+-dependent succinate transport in rat astrocytes. The inhibition constant (Ki) for the inhibition of [14C]succinate uptake by unlabeled succinate, N-acetyl-L-aspartate and citrate was 15.9, 155 and 764 microM respectively. In primary cultures of neurons, uptake of citrate was also Na+ dependent and saturable with a Kt value of 16.2 microM, which was different from that observed in astrocytes, suggesting that different Na+-dependent citrate transport systems are expressed in neurons and astrocytes. RT-PCR and immunocytochemistry revealed that NaC3 and NaC2 are expressed in cerebrocortical astrocytes and neurons respectively. These results are in good agreement with our previous reports on the brain distribution pattern of NaC2 and NaC3 mRNA using in situ hybridization. This is the first report of the differential expression of different NaCs in astrocytes and neurons. These transporters might play important roles in the trafficking of tricarboxylic acid cycle intermediates and related metabolites between glia and neurons.


Subject(s)
Astrocytes/metabolism , Cerebral Cortex/metabolism , Dicarboxylic Acid Transporters/metabolism , Neurons/metabolism , Organic Anion Transporters, Sodium-Dependent/metabolism , Sodium/metabolism , Symporters/metabolism , Animals , Animals, Newborn , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Aspartic Acid/pharmacology , Astrocytes/drug effects , Biological Transport, Active/drug effects , Biological Transport, Active/physiology , Cells, Cultured , Citric Acid/metabolism , Citric Acid Cycle/drug effects , Citric Acid Cycle/physiology , Dicarboxylic Acid Transporters/drug effects , Lithium/pharmacology , Neurons/drug effects , Organic Anion Transporters, Sodium-Dependent/drug effects , Rats , Rats, Wistar , Sodium/pharmacology , Succinic Acid/metabolism , Symporters/drug effects
11.
Biochim Biophys Acta ; 1641(1): 65-70, 2003 Jun 17.
Article in English | MEDLINE | ID: mdl-12788230

ABSTRACT

Osteoclasts dissolve mineralized bone matrix at bone resorption sites and release large amounts of calcium (Ca(2+)) and phosphate (PO(4)(3-)) ions into the extracellular fluid. However, the exact nature of Ca(2+) and PO(4)(3-) on osteoblasts remains unclear. We proposed that Ca(2+) and PO(4)(3-) ions are required for the expression of sodium-dependent vitamin C transporter (SVCT) 2 and a differentiation marker, osteopontin (OPN), in osteoblasts as a response to the osteoclastic degradation. Results from Northern blotting indicated that a deficiency of Ca(2+) or PO(4)(3-) inhibited both SVCT2 and OPN expression in a time-dependent manner, whereas elevated Ca(2+) (1 to 4 mM) or PO(4)(3-) (1 to 4 mM) dose-dependently induced SVCT2, OPN expression and OPN promoter activity. In addition, the L-type calcium channel blocker, nifedipine (5 to 20 micro M) and the phosphate transporter inhibitor, foscarnet (0.15 to 0.6 mM), dose-dependently abolished Ca(2+)- and PO(4)(3-)-induced SVCT2, OPN expression and OPN promoter activity. Furthermore, the results from L-ascorbic acid uptake assay and Western blotting indicated that the stimulatory effect of Ca(2+) and PO(4)(3-) on functional SVCT2 protein expression. These findings suggested that Ca(2+) and PO(4)(3-) regulate osteoblastic phenotype by entering into cells to stimulate SVCT2 and OPN expression.


Subject(s)
Calcium/physiology , Organic Anion Transporters, Sodium-Dependent/metabolism , Osteoblasts/metabolism , Phosphates/physiology , Sialoglycoproteins/metabolism , Symporters/metabolism , Animals , Biomarkers , Calcium Channel Blockers/pharmacology , Calcium Channels, L-Type/drug effects , Calcium Channels, L-Type/metabolism , Cell Line , Dose-Response Relationship, Drug , Foscarnet/pharmacology , Mice , Nifedipine/pharmacology , Organic Anion Transporters, Sodium-Dependent/drug effects , Osteoblasts/cytology , Osteoblasts/drug effects , Osteopontin , Sodium-Coupled Vitamin C Transporters , Symporters/drug effects
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