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Trompier D Baubichon-Cortay H Chang XB Maitrejean M Barron D Riordon JR Di Pietro A 《Cellular and molecular life sciences : CMLS》2003,60(10):2164-2177
Recombinant nucleotide-binding domains (NBDs) from human multidrug resistance protein MRP1 were overexpressed in bacteria and purified to measure their direct interaction with high-affinity flavonoids, and to evaluate a potential correlation with inhibition of MRP1-mediated transport activity and reversion of cellular multidrug resistance. Among different classes of flavonoids, dehydrosilybin exhibited the highest affinity for both NBDs, the binding to N-terminal NBD1 being prevented by ATP. Dehydrosilybin increased vanadate-induced 8-N3-[-32P]ADP trapping, indicating stimulation of ATPase activity. In contrast, dehydrosilybin strongly inhibited leukotriene C4 (LTC4) transport by membrane vesicles from MRP1-transfected cells, independently of reduced glutathione, and chemosensitized cell growth to vincristine. Hydrophobic C-isoprenylation of dehydrosilybin increased the binding affinity for NBD1, but outsite the ATP site, lowered the increase in vanadate-induced 8-N3-[-32P]ADP trapping, weakened inhibition of LTC4 transport which became glutathione dependent, and induced some cross-resistance. The overall results indicate multiple binding sites for dehydrosilybin and its derivatives, on both cytosolic and transmembrane domains of MRP1.Received 1 May 2003; received after revision 18 June 2003; accepted 24 June 2003 相似文献
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Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters 总被引:9,自引:0,他引:9
Di Pietro A Conseil G Pérez-Victoria JM Dayan G Baubichon-Cortay H Trompier D Steinfels E Jault JM de Wet H Maitrejean M Comte G Boumendjel A Mariotte AM Dumontet C McIntosh DB Goffeau A Castanys S Gamarro F Barron D 《Cellular and molecular life sciences : CMLS》2002,59(2):307-322
Cancer cell resistance to chemotherapy is often mediated by overexpression of P-glycoprotein, a plasma membrane ABC (ATP-binding cassette) transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. P-glycoprotein (ABCB1, according to the human gene nomenclature committee) consists of two homologous halves each containing a transmembrane domain (TMD) involved in drug binding and efflux, and a cytosolic nucleotide-binding domain (NBD) involved in ATP binding and hydrolysis, with an overall (TMD-NBD)2 domain topology. Homologous ABC multidrug transporters, from the same ABCB family, are found in many species such as Plasmodiumfalciparum and Leishmania spp. protozoa, where they induce resistance to antiparasitic drugs. In yeasts, some ABC transporters involved in resistance to fungicides, such as Saccharomyces cerevisiae Pdr5p and Snq2p, display a different (NBD-TMD)2 domain topology and are classified in another family, ABCG. Much effort has been spent to modulate multidrug resistance in the different species by using specific inhibitors, but generally with little success due to additional cellular targets and/or extrusion of the potential inhibitors. This review shows that due to similarities in function and maybe in three-dimensional organization of the different transporters, common potential modulators have been found. An in vitro 'rational screening' was performed among the large flavonoid family using a four-step procedure: (i) direct binding to purified recombinant cytosolic NBD and/or full-length transporter, (ii) inhibition of ATP hydrolysis and energy-dependent drug interaction with transporter-enriched membranes, (iii) inhibition of cell transporter activity monitored by flow cytometry and (iv) chemosensitization of cell growth. The results indicate that prenylated flavonoids bind with high affinity, and strongly inhibit drug interaction and nucleotide hydrolysis. As such, they constitute promising potential modulators of multidrug resistance. 相似文献
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Hall N Pain A Berriman M Churcher C Harris B Harris D Mungall K Bowman S Atkin R Baker S Barron A Brooks K Buckee CO Burrows C Cherevach I Chillingworth C Chillingworth T Christodoulou Z Clark L Clark R Corton C Cronin A Davies R Davis P Dear P Dearden F Doggett J Feltwell T Goble A Goodhead I Gwilliam R Hamlin N Hance Z Harper D Hauser H Hornsby T Holroyd S Horrocks P Humphray S Jagels K James KD Johnson D Kerhornou A Knights A Konfortov B Kyes S Larke N Lawson D Lennard N Line A Maddison M 《Nature》2002,419(6906):527-531
Since the sequencing of the first two chromosomes of the malaria parasite, Plasmodium falciparum, there has been a concerted effort to sequence and assemble the entire genome of this organism. Here we report the sequence of chromosomes 1, 3-9 and 13 of P. falciparum clone 3D7--these chromosomes account for approximately 55% of the total genome. We describe the methods used to map, sequence and annotate these chromosomes. By comparing our assemblies with the optical map, we indicate the completeness of the resulting sequence. During annotation, we assign Gene Ontology terms to the predicted gene products, and observe clustering of some malaria-specific terms to specific chromosomes. We identify a highly conserved sequence element found in the intergenic region of internal var genes that is not associated with their telomeric counterparts. 相似文献
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Simple pictorial arguments can demonstrate that the natural and Faraday rotation experiments conserve parity and time-reversal invariance. The method can be used to predict possible new effects without recourse to mathematical theories. 相似文献