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.
Sasawatari
Shigemi
S
Laboratory of Pathobiochemistry, School of Veterinary Medicine, Azabu University, Sagamihara, Kanagawa, Japan.
Toki
Minae
M
Horie
Takebumi
T
Nakano
Yuki
Y
Ikeda
Teruo
T
Ueda
Kazumitsu
K
Fujise
Hiroshi
H
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