Effect of polycyclic aromatic hydrocarbons on generation and efflux of glutathione conjugates in primary cultured alveolar epithelial cells.
This study was initiated to functionally characterize multidrug resistance associated protein (MRP)-mediated transport across the lung epithelium. Alveolar type II cells were isolated from rabbit lung and cultured on Transwell until forming a tight monolayers. After the cell monolayer was preloaded with monochlorobimane (mBCl) that is metabolized to a fluorescent glutathione conjugate (mBCl-SG), amount of mBCl-SG exported to apical and basal compartments were measured periodically. mBCl-SG was more preferentially exported in the apical direction than in the basolateral direction. Efflux of mBCl-SG from alveolar epithelial cells was significantly inhibited by a MRP inhibitor MK-571. Pharmacokinetic analysis of efflux profiles revealed that increased efflux of mBCl-SG by B[a]P is not due to enhanced MRP activity but simply due to an elevated level of mBCl-SG in the cells. Elevation of the intracellular level of mBCl-SG corresponded well to that of reduced GSH caused by B[a]P pretreatment.
Nagayoshi
Keiko
K
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Nemoto
Takayuki
T
Yokoyama
Shumpei
S
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M
D000465:Algorithms; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism; D002478:Cells, Cultured; D018432:Drug Resistance, Multiple; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits
D009153:Mutagens; D011084:Polycyclic Aromatic Hydrocarbons; D001564:Benzo(a)pyrene; D005978:Glutathione