Dataset Information

Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin.

ABSTRACT: Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter-overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance-associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 ?M (OCT1 inhibition by allethrin) to 77.6 ?M (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 ?M did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can act as regulators of the activity of various ABC and SLC drug transporters, but only when used at high and non-relevant concentrations, making unlikely any contribution of these transporter activity alterations to pyrethroid toxicity in environmentally exposed humans.

SUBMITTER: Chedik L

PROVIDER: S-EPMC5242521 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin.

Chedik Lisa L Bruyere Arnaud A Le Vee Marc M Stieger Bruno B Denizot Claire C Parmentier Yannick Y Potin Sophie S Fardel Olivier O

PloS one 20170118 1

Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrie ...[more]

PMID: 28099443

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Project description:BackgroundOrganophosphates and pyrethroids are the most common classes of insecticides used in the United States. Widespread use of these compounds to control building infestations in New York City (NYC) may have caused higher exposure than in less-urban settings.ObjectivesThe objectives of our study were to estimate pesticide exposure reference values for NYC and identify demographic and behavioral characteristics that predict exposures.MethodsThe NYC Health and Nutrition Examination Survey was a population-based, cross-sectional study conducted in 2004 among adults ? 20 years of age. It measured urinary concentrations of organophosphate metabolites [dimethylphosphate (DMP), dimethylthiophosphate (DMTP), dimethyldithiophosphate, diethylphosphate, diethylthiophosphate, and diethyldithiophosphate] in 883 participants, and pyrethroid metabolites [3-phenoxybenzoic acid (3-PBA), trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (trans-DCCA), 4-fluoro-3-phenoxybenzoic acid, and cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid] in 1,452 participants. We used multivariable linear regression to estimate least-squares geometric mean total dialkylphospate (?DAP) and 3-PBA concentrations across categories of predictors.ResultsThe dimethyl organophosphate metabolites had the highest 95th percentile concentrations (87.4 ?g/L and 74.7 ?g/L for DMP and DMTP, respectively). The highest 95th percentiles among pyrethroid metabolites were measured for 3-PBA and trans-DCCA (5.23 ?g/L and 5.94 ?g/L, respectively). Concentrations of ?DAP increased with increasing age, non-Hispanic white or black compared with Hispanic race/ethnicity, professional pesticide use, and increasing frequency of fruit consumption; they decreased with non-green vegetable consumption. Absolute differences in geometric mean urinary 3-PBA concentrations across categories of predictors were too small to be meaningful.ConclusionEstimates of exposure to pyrethroids and dimethyl organophosphates were higher in NYC than in the United States overall, underscoring the importance of considering pest and pesticide burdens in cities when formulating pesticide use regulations.

Project description:In recent years, pyrethroids have emerged as a less toxic alternative to eliminate insect pests. However, some animal studies and studies with children show that these pesticides are toxic and lead to neurobehavioral effects similar to other pesticides, such as organophosphates. The purpose of this review was to systematize the epidemiological scientific evidence about the neurobehavioral, neuromotor, and neurocognitive effects in agricultural workers and their children exposed to pyrethroid pesticides. We conducted two searches (with different terms) in PubMed and Scopus databases, including articles in Spanish and English language on the effects of occupational exposure to pyrethroid pesticides associated with neurobehavioral, neuromotor, and neurocognitive functioning of agricultural workers and their children. There were no filters by year, and the search included studies till march 2021. To develop the search, we followed the recommendations contained in the PRISMA guidelines and the PICO strategy. The results show that in 66.6% of the studies reviewed (8 of 12 studies), agricultural workers or their children occupationally exposed to pyrethroid pesticides have a higher risk of presenting difficulties in their neurocognitive, neuromotor, or neurobehavioral performance, mainly associated with attention, processing speed (linked to hand-eye coordination), and motor coordination. There are still few studies that address this issue. However, the quality of most of the research conducted (83% intermediate or high quality) confirms the risk for neurobehavioral health in agricultural workers due to occupational exposure to pyrethroids. More research is required evaluating the exposure to pyrethroids, including biomarkers and validated neurobehavioral and neuromotor tests, in addition to evaluating the effect of simultaneous exposure to other hazardous pesticides. Assuming that the use of pyrethroids is increasing considerably and faster than the scientific evidence, it is suggested as a precautionary principle to regulate, more strictly, the sale of pyrethroids and other pesticides.

Dataset Information

Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin.

Publications

Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin.

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