P-glycoprotein, multidrug resistance-related proteins (MRPs) and lung resistance-related protein (LRP) are involved in multidrug resistance in tumor cells but are also expressed in normal tissues. In the LLC-PK1 tubular renal cell line, a 15-day treatment with 25 AM rifampicin significantly increased the mRNA levels of P-glycoprotein, MRP1, MRP2, LRP and cytochrome P450 3A4 (CYP 3A4). Western blot analysis confirmed a moderate increase in the expression of P-glycoprotein and MRP2, but not MRP1 also at the protein level. The intracellular uptake of doxorubicin was significantly lower in rifampicin pretreated cells. A pretreatment with 6-[82S,4R,6E)-4-methyl-2- (methylamino)-3-oxo-6-octenoic acid]cyclosporin D, valspodar (PSC 833), a specific inhibitor of P-glycoprotein, with (3-(3-(2-(7-chloro-2- quinidinyl)ethenyl-phenyl)((3-diimethyl amino-3oxo propyl)thio)methyl)thio)propanoic acid, sodium salt (MK-571), a specific inhibitor of MRP1, and with verapamil, that inhibits both proteins, significantly increased doxorubicin cell accumulation in rifampicin pretread cells. In rifampicin treated cells cultured on porous membranes, doxorubicin showed a polarized transport, that was reduced by a pretreatment with PSC 833. A chronic treatment with rifampicin induces the expression of transport proteins and of CYP 3A4 and could therefore alter the renal elimination kinetics of drugs that are their substrates.

Induction of proteins involved in multidrug resistance (P-glycoprotein, MRP1, MRP2, LRP) and of CYP 3A4 by rifampicin in LLC-PK1 cells.

BARTOLI, FIORA;CANDUSSIO, LUIGI;GIRALDI, TULLIO;DECORTI, GIULIANA
2004

Abstract

P-glycoprotein, multidrug resistance-related proteins (MRPs) and lung resistance-related protein (LRP) are involved in multidrug resistance in tumor cells but are also expressed in normal tissues. In the LLC-PK1 tubular renal cell line, a 15-day treatment with 25 AM rifampicin significantly increased the mRNA levels of P-glycoprotein, MRP1, MRP2, LRP and cytochrome P450 3A4 (CYP 3A4). Western blot analysis confirmed a moderate increase in the expression of P-glycoprotein and MRP2, but not MRP1 also at the protein level. The intracellular uptake of doxorubicin was significantly lower in rifampicin pretreated cells. A pretreatment with 6-[82S,4R,6E)-4-methyl-2- (methylamino)-3-oxo-6-octenoic acid]cyclosporin D, valspodar (PSC 833), a specific inhibitor of P-glycoprotein, with (3-(3-(2-(7-chloro-2- quinidinyl)ethenyl-phenyl)((3-diimethyl amino-3oxo propyl)thio)methyl)thio)propanoic acid, sodium salt (MK-571), a specific inhibitor of MRP1, and with verapamil, that inhibits both proteins, significantly increased doxorubicin cell accumulation in rifampicin pretread cells. In rifampicin treated cells cultured on porous membranes, doxorubicin showed a polarized transport, that was reduced by a pretreatment with PSC 833. A chronic treatment with rifampicin induces the expression of transport proteins and of CYP 3A4 and could therefore alter the renal elimination kinetics of drugs that are their substrates.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11368/1694992
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