Effect of organophosphate pesticide diazinon on expression and activity of intestinal P-glycoprotein.
Organophosphate insecticide diazinon is widely used in agricultural practices, submitting farmers to repeated exposure. Because efflux pumps, as P-glycoprotein (P-gp), serve both as natural defense mechanisms and influence the bioavailability and disposition of drugs, we analyzed the ability of diazinon to act as efflux modulator. Oral administration of diazinon (2-20 mg/kg, 5 days, or 10 mg/kg, 2-12 days) increased intestinal mdr1a mRNA of rats, in both dose- and time-dependent manner, and increased the expression of intestinal P-gp. Using the intestinal cell-line Caco-2, we found that 100 microM diazinon significantly inhibited digoxin and vinblastine secretive flux through the cell monolayers, whereas digoxin and vinblastine absorptive flux increased. The 25 microM diazinon was transported preferentially in basolateral (BL) to apical (AP) direction, suggesting a net secretion. The efflux rate significantly decreased in the presence of metabolic inhibitors sodium azide and 2-deoxy-d-glucose, P-gp inhibitors cyclosporin A and valspodar, but not in the presence of MRPs inhibitor MK571. Repeated exposure of Caco-2 cells to diazinon increased P-glycoprotein expression and activity. These results suggested the involvement of P-gp in the transfer of diazinon, leading to potential consequences for xenobiotic interactions, and showed that repeated exposure to low doses of pesticide may lead to up-regulated P-gp functions in the intestine of mammals.
Lecoeur
Sylvaine
S
UMR INRA-DGER Métabolisme et Toxicologie Comparée des Xénobiotiques, Ecole Nationale Vétérinaire de Lyon, 1, av. Bourgelat, BP 83, F-69280 Marcy l'Etoile, France. s.lecoeur@vet-lyon.fr
Videmann
Bernadette
B
Mazallon
Michèle
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D003524:Cyclosporins / Q000494:pharmacology; D003976:Diazinon / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007306:Insecticides / Q000493:pharmacokinetics / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D003524:Cyclosporins; D004791:Enzyme Inhibitors; D007306:Insecticides; D012333:RNA, Messenger; C095122:multidrug resistance protein 3; C070272:valspodar; D003976:Diazinon