Risk assessment of the chiral pesticide fenamiphos in a human model: Cytochrome P450 phenotyping and inhibition studies

Albuquerque, Nayara Cristina Perez de; Carrão, Daniel Blascke; Habenschus, Maísa Daniela; Fonseca, Franciele Saraiva; Silva, Rodrigo Moreira da; Lopes, Norberto Peporine; Rocha, Bruno Alves; Júnior, Fernando Barbosa; Oliveira, Anderson Rodrigo Moraes de

doi:10.1016/j.fct.2020.111826

Cited by 10 publications

(4 citation statements)

References 48 publications

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“…Iprobenfos (IBF) and tribufos (TBS) also contain P–S bonds, although their metabolism by CYP2C19 was not evaluated. FMP does not contain a P–S bond like EPP but still contains a sulfur (Figure S4C) that is converted to a sulfoxide in human liver microsomes, though not by CYP2C19. , Interestingly, while FMP, IBF, and TBS were all inhibitors in our screen, EPP was not (Figure ). However, both EPP and FMP were in the short list of compounds that showed a difference in our time-dependent inhibition studies (Figure ).…”

contrasting

confidence: 99%

Human CYP2C19 Substrate and Inhibitor Characterization of Organophosphate Pesticides

Vignaux,

Shriwas,

Revnew

et al. 2023

Chem. Res. Toxicol.

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CYP2C19 is an important enzyme for organophosphate pesticide (OPP) metabolism. Because the OPPs can be both substrates and inhibitors of CYP2C19, we screened 45 OPPs for their ability to inhibit the activity of this enzyme and investigated the role of CYP2C19 in the metabolism of 22 of these molecules. We identified several nanomolar inhibitors of CYP2C19 as well as determined that thions, in general, are more potent inhibitors than oxons. We also determined that thions are readily metabolized by CYP2C19, although we saw no relationship between IC 50 values and intrinsic clearance rates. This study may have implications for mitigating the risk of OPP poisoning.

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contrasting

confidence: 99%

Human CYP2C19 Substrate and Inhibitor Characterization of Organophosphate Pesticides

Vignaux,

Shriwas,

Revnew

et al. 2023

Chem. Res. Toxicol.

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“…In general, cytochromes are very often recruited within the body to detoxify various toxicants and/or xenobiotics [10,68]. Therefore, their effect on OPCs can be nonspecific, and their activity can be greatly reduced in comparison with other substrates or even inhibited by OPC alone [69] or in combination with other substances [70]. Nevertheless, compounds of a wide subclass of OPCs containing P=S bond (e.g., parathion [71], phosmet [72], diazinon [73], etc.)…”

Section: Cytochromementioning

confidence: 99%

Enzymes, Reacting with Organophosphorus Compounds as Detoxifiers: Diversity and Functions

Lyagin

Ефременко

2021

IJMS

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Organophosphorus compounds (OPCs) are able to interact with various biological targets in living organisms, including enzymes. The binding of OPCs to enzymes does not always lead to negative consequences for the body itself, since there are a lot of natural biocatalysts that can catalyze the chemical transformations of the OPCs via hydrolysis or oxidation/reduction and thereby provide their detoxification. Some of these enzymes, their structural differences and identity, mechanisms, and specificity of catalytic action are discussed in this work, including results of computational modeling. Phylogenetic analysis of these diverse enzymes was specially realized for this review to emphasize a great area for future development(s) and applications.

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“…Gao et al reported that the acute toxicity of ( R )-isofenphos-methyl to Eisenia fetida is ∼4 times that of ( S )-isofenphos-methyl, the toxicity of racemic isofenphos-methyl originates mainly from ( R )-isofenphos-methyl’s toxicity contribution, and the proportion reaches 79.9%; hence, the enantioselective factor should be considered in environmental risk assessment. The findings of toxicological studies by de Albuquerque et al unraveled that fenamiphos enantiomers are metabolized primarily by cytochrome P450 (CYP) 3A4 and CYP 2E1 in the human body, while racemic fenamiphos is metabolized mainly by CYP 2B6, which greatly increases the health risk of chiral fenamiphos to humans; however, the molecular mechanism responsible for this phenomenon is still vague. The study reported by Li et al , verified that (1 S ,3 R )-fosthiazate has the strongest acute toxicity to honeybees, which is ∼10 times that of (1 R ,3 S )-fosthiazate, and in the meantime, (1 R ,3 R )-fosthiazate and (1 R ,3 S )-fosthiazate has almost no biological activity on target insects, but has moderate toxicity on honeybees, which is related closely to the existence of two chiral centers in fosthiazate and its toxic mode of action with the target receptor AChE.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the Enantioselective Neurotoxicity of Isocarbophos: Chiral Insight from Cellular, Molecular, and Computational Investigations

Wang

Peng

et al. 2023

Chem. Res. Toxicol.

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Chiral organophosphorus pollutants are found abundantly in the environment, but the neurotoxicity risks of these asymmetric chemicals to human health have not been fully assessed. Using cellular, molecular, and computational toxicology methods, this story is to explore the static and dynamic toxic actions and its stereoselective differences of chiral isocarbophos toward SH-SY5Y nerve cells mediated by acetylcholinesterase (AChE) and further dissect the microscopic basis of enantioselective neurotoxicity. Cell-based assays indicate that chiral isocarbophos exhibits strong enantioselectivity in the inhibition of the survival rates of SH-SY5Y cells and the intracellular AChE activity, and the cytotoxicity of (S)-isocarbophos is significantly greater than that of (R)-isocarbophos. The inhibitory effects of isocarbophos enantiomers on the intracellular AChE activity are dose-dependent, and the half-maximal inhibitory concentrations (IC50) of (R)-/(S)-isocarbophos are 6.179/1.753 μM, respectively. Molecular experiments explain the results of cellular assays, namely, the stereoselective toxic actions of isocarbophos enantiomers on SH-SY5Y cells are stemmed from the differences in bioaffinities between isocarbophos enantiomers and neuronal AChE. In the meantime, the modes of neurotoxic actions display that the key amino acid residues formed strong noncovalent interactions are obviously different, which are related closely to the molecular structural rigidity of chiral isocarbophos and the conformational dynamics and flexibility of the substrate binding domain in neuronal AChE. Still, we observed that the stable “sandwich-type π–π stacking” fashioned between isocarbophos enantiomers and aromatic Trp-86 and Tyr-337 residues is crucial, which notably reduces the van der Waals’ contribution (ΔG vdW) in the AChE–(S)-isocarbophos complexes and induces the disparities in free energies during the enantioselective neurotoxic conjugations and thus elucidating that (S)-isocarbophos mediated by synaptic AChE has a strong toxic effect on SH-SY5Y neuronal cells. Clearly, this effort can provide experimental insights for evaluating the neurotoxicity risks of human exposure to chiral organophosphates from macroscopic to microscopic levels.

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Risk assessment of the chiral pesticide fenamiphos in a human model: Cytochrome P450 phenotyping and inhibition studies

Cited by 10 publications

References 48 publications

Human CYP2C19 Substrate and Inhibitor Characterization of Organophosphate Pesticides

Human CYP2C19 Substrate and Inhibitor Characterization of Organophosphate Pesticides

Enzymes, Reacting with Organophosphorus Compounds as Detoxifiers: Diversity and Functions

Dissecting the Enantioselective Neurotoxicity of Isocarbophos: Chiral Insight from Cellular, Molecular, and Computational Investigations

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