Effect of nonylphenol ethoxylates (NPEs) on barrier functions of epithelial cell membranes: opening of tight junctions and competitive inhibition of P-gp-mediated efflux.
The effect of nonylphenol ethoxylates (NPEs) on selected barrier functions of biological membranes, such as tight junction and P-gp efflux pump of epithelial membranes, against the transport of xenobiotics was examined. The Caco-2 cell line was used to evaluate the transport of mannitol and daunomycin across the cell monolayer as well as the cellular uptake of daunomycin. In the presence of NPEs, the transport of mannitol was increased, with NP-9 showing a maximal effect, and the transepithelial electrical resistance (TEER) was reduced. The onset of this effect of NP-9 was fairly rapid and reversible for a short term (e.g., 2 h) treatment, while irreversible for a long term (e.g., 72 h) treatment. In the presence of NP-9, the apical uptake of daunomycin was increased, suggesting competitive inhibition between NP-9 and daunomycin in the efflux via the P-gp system. However, a 72 h pretreatment of the cells with NP-9 (up to 1000 nM) did not affect the apparent cellular uptake of daunomycin, suggesting no significant effect of NPEs on the expression of P-gp. In conclusion, NPEs appear to rapidly open the tight junction of epithelial cell membranes and to competitively inhibit the efflux of P-gp substrates, thereby reducing the self-protection ability of the organism against xenobiotics or hazardous environmental compounds that are transported via the paracellular pathway (i.e., uptake) or the P-gp system (i.e., efflux).
Doo
Min-Ho
MH
Department of Pharmaceutics, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Li
Hong
H
Jang
Hye-In
HI
Song
Im-Sook
IS
Chung
Suk-Jae
SJ
Shim
Chang-Koo
CK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002250:Carbon Radioisotopes; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D003630:Daunorubicin / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005026:Ethylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008353:Mannitol / Q000493:pharmacokinetics; D015394:Molecular Structure; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014316:Tritium
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D005026:Ethylene Glycols; D014316:Tritium; C021754:terics; D008353:Mannitol; D003630:Daunorubicin