Combined in silico and in vitro approaches to identify P-glycoprotein-inhibiting pesticides.
J Biochem Mol Toxicol
; 38(1): e23588, 2024 Jan.
Article
in En
| MEDLINE
| ID: mdl-37985955
ABSTRACT
The P-glycoprotein (P-gp) efflux pump plays a major role in xenobiotic detoxification. The inhibition of its activity by environmental contaminants remains however rather little characterised. The present study was designed to develop a combination of different approaches to identify P-gp inhibitors among a large number of pesticides using in silico and in vitro models. First, the prediction performance of four web tools was evaluated alone or in combination using a set of recently marketed drugs. The best combination of web tools-AdmetSAR2.0/PgpRules/pkCSM-was next used to predict P-gp activity inhibition by 762 pesticides. Among the 187 pesticides predicted to be P-gp inhibitors, 11 were tested in vitro for their ability to inhibit the efflux of reference substrates (rhodamine 123 and Hoechst 33342) in P-gp overexpressing MCF7R cells and to inhibit the efflux of the reference substrate rhodamine 123 in the Caco-2 cell monolayer. In MCF7R cell assays, ivermectin B1a, emamectin B1 benzoate, spinosad, dimethomorph and tralkoxydim inhibited P-gp activity; ivermectin B1a, emamectin B1 benzoate and spinosad were determined to be stronger inhibitors (half-maximal inhibitory concentration [IC50 ] of 3 ± 1, 5 ± 1 and 7 ± 1 µM, respectively) than dimethomorph and tralkoxydim (IC50 of 102 ± 7 and 88 ± 7 µM, respectively). Ivermectin B1a, emamectin B1 benzoate, spinosad and dimethomorph also inhibited P-gp activity in Caco-2 cell monolayer assays, with dimethomorph being a weaker P-gp inhibitor. These combined approaches could be used to identify P-gp inhibitors among food contaminants, but need to be optimised and adapted for high-throughput screening.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pesticides
/
ATP Binding Cassette Transporter, Subfamily B, Member 1
/
Cyclohexanones
/
Disaccharides
/
Imines
Limits:
Humans
Language:
En
Journal:
J Biochem Mol Toxicol
Journal subject:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
TOXICOLOGIA
Year:
2024
Type:
Article
Affiliation country:
France