In vitro detection of the MDR phenotype in rat myocardium: use of PCR, [3H]daunomycin and MDR reversing agents.
A decrease in the intracellular drug concentration in resistant cells as compared to sensitive cells is one of the characteristics of the MDR phenotype. P-glycoprotein (Pgp) is thought to be responsible for an active efflux of some lipophilic drugs such as anthracyclines. Anthracyclines such as daunomycin are highly effective anticancer agents but induce a well-described, while incompletely explained, cardiac toxicity. In this study, we investigated the MDR phenotype in rat myocardium in terms of gene expression, detection of Pgp and indirect evaluation of Pgp function. A clear mdr1a gene specific expression in rat cultured myocardial cells and cardiac tissue was detected by RT-PCR. The incorporation of [3H]daunomycin in myocardial cell cultures was studied with and without reversing agents. Daunomycin was found to have a high accumulation in cardiac cells illustrated by a Ci/Ce ratio of 2890. This high accumulation was moderately but significantly (p < 0.05) increased in the presence of a MDR reversing agent such as verapamil, PSC 833 or S9788. These results suggest that blockade of the Pgp in humans may result in an increased toxicity of several Pgp substrates in normal tissues like the myocardium.
Cayre
A
A
Laboratoire de Transfert, Centre Jean Perrin, Clermont-Ferrand, France.
Moins
N
N
Finat-Duclos
F
F
Maublant
J
J
Albuisson
E
E
Verrelle
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D003630:Daunorubicin / Q000378:metabolism / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D019450:Genes, MDR / Q000187:drug effects* / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003630:Daunorubicin