P Borst

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..This review summarizes recent work on the mechanism of site switching and on the way inactive expression sites are kept silent...

..The physiologic functions of the other MRPs are not known. Whether long-term inhibition of MRPs in humans can be tolerated (assuming that suitable inhibitors will be found) remains to be determined...

..A third example, the ABC transporter involved in the import of long-chain fatty acids into peroxisomes, is discussed in the chapter by Hettema and Tabak in this volume...

..This mechanism can be accompanied by other resistance mechanisms, such as reduced topo II alpha mRNA in case of doxorubicin selection...

..This implies that ethacrynic acid may modulate drug resistance of tumor cells not only by inhibiting glutathione S-transferase activity, but also by inhibiting the export of drug conjugates from the cell by MRP...

..Our results indicate that Mrp1 helps to limit tissue distribution of certain drugs and contributes to the blood-CSF drug-permeability barrier...

..Unexpectedly, export of the organic anion calcein by MDCKII-MRP1 and MDCKII-MRP2 cells is stimulated by Pluronic L61, probably because it relieves the block on entry of calcein AM into the cell by endogenous MDR1 Pgp...

..We conclude that cMOAT is a 5'-adenosine triphosphate binding cassette transporter that potentially might be involved in drug resistance in mammalian cells...

..We discuss the possible function of MRP3 in (hepatic) physiology and its potential contribution to drug resistance of cancer cells...

..We speculate that MRP5 might play a role in some cases of unexplained resistance to thiopurines in acute lymphoblastic leukemia and/or to antiretroviral nucleoside analogs in HIV-infected patients...

..Our results emphasize the need for gene-specific blocks in gene expression to define which transporter contributes to resistance in each resistant cell line...

..We discuss how PC might reach the canalicular membrane of the hepatocyte for secretion into the bile, if not by Pc-tp...

..mdr1a/1b (-/-) mice should provide a useful model system to further test the pharmacological roles of the drug-transporting P-gps and to analyze the specificity and effectivity of P-gp-blocking drugs...

..In the present study, we have isolated the human homologue of rat cmoat, human cMOAT, and analyzed the corresponding cDNA from fibroblasts of a DJS patient for mutations. Our results show that a mutation in this gene is the cause of DJS...

..Even though etoposide glucuronide is an excellent substrate for MRP3, this compound is not involved in the etoposide resistance of our MRP3 cells, as these cells extrude unmodified etoposide rather than etoposide glucuronide...

..We conclude that mouse erythrocytes contain at least two transport systems for PGA2-GS. One of these is mrp1; the other one has not been identified yet, but can be inhibited by methotrexate and cAMP...

..We speculate that these effects are mediated by the packaging of J-containing DNA into a condensed chromatin structure...

..Our results suggest that MRP6 does not play a role in the resistance of the resistant cells analyzed, and that MRP6/ARA is only coamplified with MRP1 because of its location immediately next to it on the same chromosome...

..The promoter region contains several consensus sequences where known or putative liver-specific (C/EBP, HNF5) or lymphoid specific (Pu.1, ets-1) transcription factors may bind...

..However, at high sulfinpyrazone concentrations this compound is transported without GSH. Models of MRP action are discussed that could explain these results...

..The excretion of cholesterol is not tightly coupled to the excretion of phospholipids in these mice, because a very low phospholipid excretion level is sufficient to give almost wild-type cholesterol excretion into the bile...

..In the TR(-) rat, a single-nucleotide deletion in this gene resulted in a reduced messenger RNA level and absence of the protein. It is likely that this mutation accounts for the TR(-) phenotype...

..Our results indicate that specific inhibitors of MRP1 used to reverse MDR, in combination with carcinostatic drugs transported by MRP1, might lead to drug-induced mucositis, (temporary) infertility, and diabetes insipidus...

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..The MDR1 Pgp can transport drugs; the murine homologue of MDR3, mdr2, was recently shown by us to be involved in transport of the phospholipid phosphatidylcholine (lecithin) into bile...

..For some drugs, this leads to dramatically increased toxicity, indicating that P-glycoprotein inhibitors should be used with caution in patients...

..We conclude that mrp1(-/-) mice are resistant against pneumococcal pneumonia by a mechanism that involves increased release of LTB(4). These results identify mrp1 as a novel target for adjunctive therapy in pneumonia...

..Recent experiments with polarized cells support the idea that drug-transporting P-glycoproteins act by flipping drugs from the inner to the outer leaflet of the plasma membrane...

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..This genomic location at chromosome ends not only allows easy exchange of VSG gene cassettes using various mechanisms of DNA recombination but also appears to play a role in VSG gene expression site control...

..In addition to adult liver, high levels of PC-TP RNA were also found in kidney and testis. The prominent presence of PC-TP in developing and adult liver is compatible with its proposed role in bile formation...

..These results encourage further research on the development of a clinically useful oral formulation of paclitaxel...

..The fact that we pick up these normally infrequent deletions, indicates that inactivation of the old VSG expression site could be rate limiting during switching in our strain of T. brucei...

..Our results show that all major thiopurine monophosphates important in the efficacy of mercaptopurine treatment are transported by MRP4 and MRP5, although the substrate specificity of the two transporters differs in detail...

..c) A rapidly increasing number of ABC transporters are found to play a role in lipid transport. Defects in each of these transporters are involved in human inborn or acquired diseases...

..The assay we used, which measures DNA breaks as an end point of topo II activity, could be a good candidate...

..We briefly review how ABC transporters in general, and MRPs in particular, could affect the disposition and cellular accumulation of antiviral compounds...

..Analysis of the consequences of Pgp blockade has been facilitated by the generation of mice with disrupted mdr1a genes [mdr1a(-/-)]...

..We conclude that there is no unambiguous proof for co-transport of two different ligands by MRPs, but that cross-stimulated transport can explain the published data...

..Instead, we have found a role for MRP3 in the cellular export of drug-glucuronide conjugates. We discuss problems in extrapolating results obtained for murine MRPs...

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..The J-binding proteins show 43-63% identity and are unlike any known protein. The discovery of a J-binding protein suggests that J, like methylated cytosine in higher eukaryotes, functions via a protein intermediate...

..Because of its high sensitivity, it may also be useful for the detection of the low amounts of HOMedU resulting from oxidative damage of DNA...

..These results may explain a range of pharmacological interactions observed between various drugs in patients...

..80% of the amino acids are conserved between the products of mdr1 and mdr3. Although the function of mdr3 is not yet known, its high homology with mdr1 suggests that it also encodes an efflux pump with broad specificity...

..Our results suggest that this ubiquitous GS-X pump is dispensable in mice, making treatment of MDR with MRP-specific reversal agents potentially feasible...

..Since no vesicular secretion occurs at 15 degrees C, the short-chain lipids must have been translocated by the Pgps across the plasma membrane before extraction into the medium by the lipid-acceptor albumin...

..Our results indicate that yeast YCF1 is a glutathione S-conjugate pump, like MRP, and they raise the possibility that the cadmium resistance in yeast involves cotransport of cadmium with glutathione derivatives...

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..Our results confirm the central role of the mdr1 (pgp1) gene in MDR and suggest that different cross-resistance patterns are not due to differential expression of different P-glycoprotein genes...