Document Detail

Lysosomotropic agents increase vinblastine efflux from mouse MDR proximal kidney cells exhibiting vectorial drug transport.
MedLine Citation:
PMID:  10048589     Owner:  NLM     Status:  MEDLINE    
Vinblastine (VBL) transport and efflux were studied in mouse proximal tubule PKSV-PR cells and in their multidrug-resistant derivatives PKSV-PRcol50 cells. The PKSV-PRcol50 cells produced more mdr1b transcripts and had higher resistance to various drugs. PKSV-PRcol50 cells had a predominantly basal-to-apical flux of [3H]VBL, 2.7 times larger than that in PKSV-PR cells. This flux was partially inhibited by verapamil (VRP) (10 microM) and cyclosporin A (CsA) (200 nM). [3H]VBL efflux was also greater in PKSV-PRcol50 than in PKSV-PR cells. Treatment with NH4Cl (30 mM), a lysosomotropic weak base, and concanamycin A (CCM A) (20 nM), an inhibitor of the vacuolar H+/ATPase, further increased [3H]VBL efflux from PKSV-PRcol50 cells. The cytoplasmic pH (pHcyt) of these drug-resistant cells transiently increased in the presence of NH4Cl deltapHcyt: +0.4). CCM A caused a moderate, delayed increase in pHcyt (deltapHcyt: +0.1) and made the acidic intralysosomal compartment more alkaline (deltapHlys: +1.3). VRP and CsA prevented the NH4Cl- and CCM A-induced [3H]VBL efflux from PKSV-PRcol50 cells. However, VRP (10 microM) did not significantly affect pHcyt of PKSV-PRcol50 cells, the NH4Cl-and CCM A-induced pHcyt responses, and the effect of CCMA on pHlys. Thus, lysosomotropic agents may affect the kinetics of [3H]VBL efflux. Our results also suggest that the inhibitory action of VRP on VBL efflux was not directly mediated by a pH-dependent process in these drug-resistant renal proximal tubule cells.
R Lacave; Z Ouar; M Paulais; M Bens; S Ricci; F Cluzeaud; A Vandewalle
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cellular physiology     Volume:  178     ISSN:  0021-9541     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  1999 Feb 
Date Detail:
Created Date:  1999-03-15     Completed Date:  1999-03-15     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  247-57     Citation Subset:  IM    
Laboratoire d'Histologie et Biologie Tumorale, Hôpital Tenon, Paris, France.
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MeSH Terms
Ammonium Chloride / pharmacology
Base Sequence
Biological Transport, Active / drug effects
Cell Line
Cell Polarity
Concanavalin A / pharmacology
DNA Primers / genetics
Drug Resistance, Multiple / genetics
Epithelial Cells / cytology,  drug effects,  metabolism
Genes, MDR
Hydrogen-Ion Concentration
Intracellular Fluid / metabolism
Kidney Tubules, Proximal / cytology,  drug effects*,  metabolism*
Lysosomes / drug effects
P-Glycoprotein / biosynthesis,  genetics
Vinblastine / pharmacokinetics*
Reg. No./Substance:
0/DNA Primers; 0/P-Glycoprotein; 11028-71-0/Concanavalin A; 12125-02-9/Ammonium Chloride; 865-21-4/Vinblastine

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