title: Anthelmintics are substrates and activators of nematode P glycoprotein.
abstract: P glycoproteins (Pgp), members of the ABC transporter superfamily, play a major role in chemoresistance. In nematodes, Pgp are responsible for resistance to anthelmintics, suggesting that they are Pgp substrates, as they are in mammalian cells. However, their binding to nematode Pgp and the functional consequences of this interaction have not been investigated. Our study showed that levamisole and most of the macrocyclic lactones (MLs) are Pgp substrates in nematodes. Ivermectin, although a very good substrate in mammalian cells, is poorly transported. In contrast to their inhibitory effect on mammalian Pgp, these drugs had a stimulatory effect on the transport activity of the reference Pgp substrate rhodamine 123 (R123) in the nematode. This may be due to a specific sequence of nematode Pgp, which shares only 44% identity with mammalian Pgp. Other factors, such as the affinity of anthelmintics for Pgp and their concentration in the Pgp microenvironment, could also differ in nematodes, as suggested by the specific relationship observed between the octanol-water partition coefficient (log P) of MLs and R123 efflux. Nevertheless, some similarities were also observed in the functional activities of the mammalian and nematode Pgp. As in mammalian cells, substrates known to bind the H site (Hoechst 33342 and colchicine) activated the R site, resulting in an increased R123 efflux. Our findings thus show that ML anthelmintics, which inhibit Pgp-mediated efflux in mammals, activate transport activity in nematodes and suggest that several substituents in the ML structure are involved in modulating the stimulatory effect.
authors.affiliation: INRA, IASP, UR 1282, Multiresistance and Pathogenicity of Nematodes, 37380 Nouzilly, France. kerboeuf@tours.inra.fr
authors.forename: Dominique
authors.initials: D
authors.lastname: Kerboeuf
authors.forename: Fabrice
authors.initials: F
authors.lastname: Guégnard
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000871:Anthelmintics / Q000378:metabolism* / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects*; D006189:Haemonchus / Q000378:metabolism; D015801:Helminth Proteins / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000871:Anthelmintics; D015801:Helminth Proteins