Effect of PCB-126 on intracellular accumulation and transepithelial transport of vinblastine in LLC-PK1 and its transformant cells expressing human P-glycoprotein.
The effects of 3, 3', 4, 4', 5-pentachlorobiphenyl (PCB-126), which is the most toxic congener of coplanar polychlorinated biphenyls (Co-PCBs), on intracellular accumulation and transepithelial transport of vinblastine were examined in porcine kidney cells, LLC-PK1, and its transformant cells expressing human P-glycoprotein (LLC-MDR1). The accumulation decreased less than one-tenth in LLC-MDR1 compared to LLC-PK1. In both cells, the accumulation increased with the addition of PCB-126 and cyclosporine A (CYA), which are P-glycoprotein modulators, though the magnitudes were different in these two cell groups as well as for these two chemicals. Thus, PCB-126 might inhibit extrusion of vinblastine through the drug extrusion system as does CYA. In both the cells, there might be an endogenous drug extrusion system other than P-glycoprotein that was inhibited by CYA or PCB-126. The net basal-to-apical transepithelial transport of vinblastine increased 1.7-fold more in LLC-MDR1 than in LLC-PK1. By adding PCB-126 on the apical side, the transport was greatly decreased by -76% in the monolayer of both cells. By adding PCB-126 and CYA on the basal side in LLC-MDR1 monolayer, the transports increased -1.7-fold, so that PCB-126 might inhibit the extrusion of vinblastine on both the apical and basal sides. One of the causes to be considered for the adverse effects of Co-PCBs, in addition to the binding with an aryl hydrocarbon receptor, might be the modification of drug transport by its interaction with the drug transport system.
Laboratory of Pathobiochemistry, School of Veterinary Medicine, Azabu University, Sagamihara, Kanagawa, Japan.
Shigemi
S
Sasawatari
Minae
M
Toki
Takebumi
T
Horie
Yuki
Y
Nakano
Teruo
T
Ikeda
Kazumitsu
K
Ueda
Hiroshi
H
Fujise
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D012588:Scintillation Counting; D013552:Swine; D014170:Transformation, Genetic; D014316:Tritium; D014747:Vinblastine / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014316:Tritium; D014747:Vinblastine; D016572:Cyclosporine; D011078:Polychlorinated Biphenyls; C023035:3,4,5,3',4'-pentachlorobiphenyl