Ochratoxin A secretion by ATP-dependent membrane transporters in Caco-2 cells.
The ATP-dependent membrane transporters, P-gp, MRP2 and BCRP, localized in the luminal membranes of the intestines, liver and kidney, counteract absorption and increase excretion of xenobiotics and drugs. Previously, it has been suggested that the mycotoxin ochratoxin A (OTA) is a substrate for ATP-dependent transporters, and hence the absorption and secretion of OTA in the Caco-2 cell model was investigated. To this end, Caco-2 cells were cultured as confluent monolayers in bicameral inserts and the transepithelial transport of the mycotoxin was assessed. Caco-2 cells secreted OTA to the luminal side in a concentration-dependent manner. This secretory permeability was higher than the absorptive permeability, while the absorptive permeability remained constant for all OTA concentrations tested. The secretion decreased and absorption increased in the presence of the MRP-inhibitor MK571, the P-gp and BCRP inhibitor GF120918, and the BCRP-inhibitor Ko143, suggesting that the secretion of OTA is mediated by MRP2 and BCRP. Cyclosporine A also decreased the secretory permeability, but did not affect absorptive permeability, while PSC833 did neither change absorption nor secretion of OTA. Hence it can be suggested that OTA is a substrate for MRP2 as well as BCRP. These findings are of interest in evaluating mycotoxin absorption after oral ingestion, tissue distribution and particularly excretion pathways, including renal, biliary and mammary gland excretion.
Schrickx
Jan
J
Department of Veterinary Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 16, 3584 CM, Utrecht, The Netherlands, J.A.Schrickx@vet.uu.nl
Lektarau
Yuri
Y
Fink-Gremmels
J
J
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D001692:Biological Transport; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009793:Ochratoxins / Q000378:metabolism* / Q000633:toxicity; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D003524:Cyclosporins; D009793:Ochratoxins; D011422:Propionates; D011804:Quinolines; D044005:Tetrahydroisoquinolines; C025589:ochratoxin A; C059141:verlukast; D016572:Cyclosporine; C083501:Elacridar; C070272:valspodar