Effect of Chlorpyrifos on Efflux Transporter Gene Expression and Function in Caco-2 Cells

The effect of chlorpyrifos (CPF) and its metabolite, chlorpyrifos-oxon (CPO), on multidrug resistance-1 (MDR1) gene expression and efflux transporter function in Caco-2 cells was determined. The effect of CPF and CPO on gene expression in Caco-2 cells was tested as a function of time using RT-PCR an...

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Bibliographic Details
Published in:Toxicology in vitro 2004-08, Vol.18 (4), p.403-409
Main Authors: Agarwala, S, Chen, W, Cook, T.J
Format: Article
Language:English
Subjects:
ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis
Biological Availability
Caco-2 Cells
Chlorpyrifos
Chlorpyrifos - analogs & derivatives
Chlorpyrifos - toxicity
Gene Expression Regulation - drug effects
Humans
Insecticides - toxicity
Intestine
Membrane Transport Proteins - drug effects
Membrane transporter
Permeability
Reverse Transcriptase Polymerase Chain Reaction
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Summary:The effect of chlorpyrifos (CPF) and its metabolite, chlorpyrifos-oxon (CPO), on multidrug resistance-1 (MDR1) gene expression and efflux transporter function in Caco-2 cells was determined. The effect of CPF and CPO on gene expression in Caco-2 cells was tested as a function of time using RT-PCR and competitive PCR (compPCR) techniques. The RT-PCR results depicted a maximal effect of CPF exposure on MDR1 expression at 8 h, which decreased at 24 h. Studies with CPO displayed an initial increase in expression at 4 h only. The compPCR assays were conducted with the CPF-treated group to quantify the changes in gene expression levels. The compPCR data confirmed and quantitated the results from the time-course study using semiquantitative RT-PCR. In addition to the gene expression studies, changes in efflux transporter function were investigated using Caco-2 cells grown on semipermeable membranes in Transwell™ plates. The permeability of verapamil was determined in cells treated for 8 h with CPF. Efflux ratios demonstrated that verapamil was effluxed at a higher rate from the CPF-treated cells as compared to the control group, confirming the inductive action of CPF on transporter function. These results suggest that CPF has the potential to modulate the bioavailability of drugs via changes in expression and function of membrane efflux transporters.
ISSN:0887-2333
1879-3177
DOI:10.1016/j.tiv.2003.12.006