title: Specific interactions of chloroacetanilide herbicides with human ABC transporter proteins.
abstract: Chloroacetanilide herbicides are among the most commonly used herbicides in agriculture. Several studies have demonstrated a number of them to be carcinogenic. ATP binding cassette (ABC) transporters are efflux pumps expressed in cell membranes, which form an important wall of defense against xenobiotics from different sources. We tested the interaction of the herbicides acetochlor, alachlor, dimetachlor, metazachlor, metolachlor, propachlor and prynachlor with human multidrug resistance transporters MDR1, MRP1, MRP2 and BCRP. A number of metabolites were studied for interaction with MRP1, MRP2 and MRP3. Transporter interactions were studied by measuring ATPase activity, inhibition of fluorescent dye efflux and vesicular transport. Also inhibition of MDR1 was monitored by measuring digoxin transport on Caco-2 monolayers and paclitaxel toxicity on K562-MDR cells. Acetochlor, alachlor, metolachlor and metazachlor showed specific interactions with MDR1. Digoxin permeability and paclitaxel cytotoxicity studies revealed that these herbicides are potent inhibitors of MDR1 that can modulate drug absorption and cause chemosensitization of cells. MRP1 was demonstrated to transport an important intermediate of the acetochlor detoxification pathway. Several specific interactions were shown when studying the interaction of chloroacetanilides with human transporter proteins. This study suggests an important role for transporter proteins in hazard prediction of agrochemicals and demonstrates how transporter interactions can be easily detected using in vitro screening methods.
authors.affiliation: SOLVO Biotechnology, Gyár utca 2, 2040 Budaörs, Hungary. berend@solvo.com
authors.forename: Berend
authors.initials: B
authors.lastname: Oosterhuis
authors.forename: Krisztina
authors.initials: K
authors.lastname: Vukman
authors.forename: Erika
authors.initials: E
authors.lastname: Vági
authors.forename: Hristos
authors.initials: H
authors.lastname: Glavinas
authors.forename: István
authors.initials: I
authors.lastname: Jablonkai
authors.forename: Péter
authors.initials: P
authors.lastname: Krajcsi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000081:Acetamides / Q000633:toxicity*; D000083:Acetanilides / Q000633:toxicity*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004077:Digoxin / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D020014:K562 Cells; D017239:Paclitaxel / Q000633:toxicity; D014052:Toluidines / Q000633:toxicity*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000081:Acetamides; D000083:Acetanilides; D000972:Antineoplastic Agents, Phytogenic; D006540:Herbicides; D014052:Toluidines; D004077:Digoxin; C043377:acetochlor; D000251:Adenosine Triphosphatases; D017239:Paclitaxel