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Cunninghamella spp. produce mammalian-equivalent metabolites from fluorinated pyrethroid pesticides.

ABSTRACT: Cunninghamella spp. are fungi that are routinely used to model the metabolism of drugs. In this paper we demonstrate that they can be employed to generate mammalian-equivalent metabolites of the pyrethroid pesticides transfluthrin and β-cyfluthrin, both of which are fluorinated. The pesticides were incubated with grown cultures of Cunninghamella elegans, C. blakesleeana and C. echinulata and the biotransformation monitored using fluorine-19 nuclear magnetic resonance spectroscopy. Transfluthrin was initially absorbed in the biomass, but after 72 h a new fluorometabolite appeared in the supernatant; although all three species yielded this compound, it was most prominent in C. blakesleeana. In contrast β-cyfluthrin mostly remained in the fungal biomasss and only minor biotransformation was observed. Gas chromatography-mass spectrometry (GC-MS) analysis of culture supernatant extracts revealed the identity of the fluorinated metabolite of transfluthrin to be tetrafluorobenzyl alcohol, which arose from the cytochrome P450-catalysed cleavage of the ester bond in the pesticide. The other product of this hydrolysis, dichlorovinyl-2,2-dimethylcyclopropane carboxylic acid, was also detected by GC-MS and was a product of β-cyfluthrin metabolism too. Upon incubation with rat liver microsomes the same products were detected, demonstrating that the fungi can be used as models of mammalian metabolism of fluorinated pesticides.

SUBMITTER: Khan MF

PROVIDER: S-EPMC8266954 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 μM (OCT1 inhibition by allethrin) to 77.6 μM (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 μM 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.

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.

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Cunninghamella spp. produce mammalian-equivalent metabolites from fluorinated pyrethroid pesticides.

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