Myclobutanil enantioselective risk assessment in humans through in vitro CYP450 reactions: Metabolism and inhibition studies

Fonseca, Franciele Saraiva; Carrão, Daniel Blascke; Albuquerque, Nayara Cristina Perez de; Nardini, Viviani; Dias, Luís Gustavo; Silva, Rodrigo M. da; Lopes, Norberto P.; Oliveira, Anderson Rodrigo Moraes de

doi:10.1016/j.fct.2019.04.009

Cited by 40 publications

(16 citation statements)

References 37 publications

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“…3E), but the molecule was unable to pass the gate of Bay-1/ Cavity-2 residues due to the rear-side arrangement of the triazole group. These results were consistent with a report on non-substantial disappearance of the R(-)-isomer in the recombinant-CYP3A4 system 34) . Similar difference is also observed on another enzyme, CYP2C19, for oxidations of myclobutanil 34) .…”

Section: Placements Of Myclobutanil Hexaconazole and Propiconazolesupporting

confidence: 93%

“…These results were consistent with a report on non-substantial disappearance of the R(-)-isomer in the recombinant-CYP3A4 system 34) . Similar difference is also observed on another enzyme, CYP2C19, for oxidations of myclobutanil 34) . These data suggested the distinct pharmacokinetic profiles of R(-)-and S(+)-myclobutanil in humans.…”

Section: Placements Of Myclobutanil Hexaconazole and Propiconazolesupporting

confidence: 93%

“…These phenomena might underlie the profile of regioselectivity of CYP3A4-mediated oxidation of azole fungicides like propiconazole. CYP3A4 mediates oxidations of S-, but not R-myclobutanil 34) , although CYP3A4 is inhibited by both the isomers (Fig. 3).…”

Section: Discussionmentioning

confidence: 98%

“…This fungicide is metabolized extensively in rats and thus the parent chemicals represent a few percent of the total excretion 32) . Both R(-)-and S(+)-myclobutanil inhibit human CYP3A-mediated oxidations, but clear differences are detected on the rates of CYP3A4-mediated R(-)-and S(+)-myclobutanil metabolisms in vitro determined as the substrate disappearance 34) .…”

Section: Placements Of Myclobutanil Hexaconazole and Propiconazolementioning

confidence: 94%

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Prediction and Characterization of CYP3A4-mediated Metabolisms of Azole Fungicides: an Application of the Fused-grid Template* system

2020

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Human CYP3A4 is involved in metabolisms of diverse hydrophobic chemicals. Using the data of therapeutic azole fungicides known to interact with CYP3A4, applicability of CYP3A4 Template system was first confirmed to reconstitute faithfully the interaction on Template. More than twenty numbers of pesticide azoles were then applied to the Template system. All the azole stereo-isomers applied, except for talarozole, interacted through nitrogen atoms of triazole or imidazole parts and sat stably for inhibitions through fulfilling three-essential interactions. For their CYP3A4-mediated oxidations, clear distinctions were suggested among the enantiomers and diastereomers of azole pesticides on Templates. Thus, the stereoisomers would have their-own regio-and stereo-selective profiles of the metabolisms. A combined metabolic profile of each azole obtained with CYP3A4 Template system, however, resembled with the reported profile of the in vivo metabolism in rats. These results suggest the major roles of CYP3A forms on the metabolisms of most of azole pesticides in both rats and humans. Free triazole is a metabolite of azole fungicides having a methylene-spacer between triazole and the rest of the main structures in experimental animals and humans. During the simulation experiments, a placement for the oxidation of a methylene spacer between the triazole and main carbon-skeleton was found to be available throughout the azole fungicides tested on Template. The occurrence of this reaction to lead to triazole-release is thus discussed in relation to the possible involvement of CYP3A forms.

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Section: Placements Of Myclobutanil Hexaconazole and Propiconazolesupporting

confidence: 93%

Section: Placements Of Myclobutanil Hexaconazole and Propiconazolesupporting

confidence: 93%

Section: Discussionmentioning

confidence: 98%

Section: Placements Of Myclobutanil Hexaconazole and Propiconazolementioning

confidence: 94%

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Prediction and Characterization of CYP3A4-mediated Metabolisms of Azole Fungicides: an Application of the Fused-grid Template* system

2020

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“…Although myclobutanil's acute toxicity is low-its half life in grape foliage has been estimated at approximately 15 days-it has been reported recently that myclobutanil cannot be metabolized by human enzymes. In addition, when myclobutanil is consumed, it may cause various toxic health effects, such as hepatocyte hypertrophy and testicular atrophy in rodents [33,34]. It has also been reported to increase liver mixed function oxidase and to disrupt steroid hormone homeostasis [35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Effect of Myclobutanil Pesticide on the Physiological Behavior of Two Newly Isolated Saccharomyces cerevisiae Strains during Very-High-Gravity Alcoholic Fermentation

et al. 2019

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Yeasts are able to act as biosorbents, as their cell wall includes several components capable of binding organic xenobiotic compounds that can potentially be removed during various fermentation processes. In the present investigation, two novel Saccharomyces cerevisiae strains (LMBF-Y 16 and LMBF-Y-18), previously isolated from grapes, were studied regarding their physiological behavior (dry cell weight—DCW production, substrate uptake, and ethanol and glycerol biosynthesis) during fermentations of grape must, in some cases enriched with commercial glucose and fructose (initial total sugar concentration approximately 150 and 250 g/L, respectively). Myclobutanil (a chiral triazole fungicide broadly used as a protective agent of vine) was also added to the culture media at various concentrations in order to assess the ability of the yeasts to simultaneously perform alcoholic fermentations and detoxify the medium (i.e., to remove the fungicide). In the first set of experiments and for both tested strains, trials were carried out in either 250 mL or 2.0 L agitated shake flasks in either synthetic glucose-based experiments or grape musts. Since the results obtained in the trials where the cultures were placed in 2.0 L flasks with grape musts as substrates were superior in terms of both DCW and ethanol production, these experimental conditions were selected for the subsequent studies. Both strains showed high fermentative efficiency, producing high amounts of DCW (9.5–10.5 g/L) in parallel with high ethanol production, which in some cases achieved values very close to the maximum theoretical ethanol production yield (≈0.49 g of ethanol per g of sugar). When using grape must with initial total sugars at approximately 250 g/L (very high gravity fermentation media, close to winemaking conditions), significantly high ethanol quantities (i.e., ranging between 105 and 123 g/L) were produced. Myclobutanil addition slightly negatively affected sugar conversion into ethanol; however, in all cases, ethanol production was very satisfactory. A non-negligible myclobutanil removal during fermentation, which ranged between 5%–27%, as a result of the adsorptive or degradative capacity of the yeast was also reported. The presence of myclobutanil had no effect on DCW production and resulted in no significant differences in the biosynthesis of glycerol. Therefore, these newly isolated yeast strains could be excellent candidates for simultaneous high ethanol production and parallel pesticide removal in a general biorefinery concept demonstrating many environmental benefits.

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Residues determination, risk assessment, and dissipation behavior of myclobutanil formulation on apple

Amin,

Sheikh,

Jan

et al. 2024

Biomedical Chromatography

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This study aimed to investigate the dissipation pattern, risk assessment, and waiting period of myclobutanil on apple fruit (Malus domestica Borkh.) under temperate conditions in Kashmir, India. The study involved the application of myclobutanil 10 WP at a single recommended dosage (125 g a.i. ha−1) and double dosage (250 g a.i. ha−1) on Red Velox apple trees, 2 months before harvest. GC equipped with an electron capture detector was used to analyze myclobutanil residues in fruit samples. The study revealed that myclobutanil, at both recommended and double recommended doses, dissipated rapidly and became nondetectable after 55 and 60 days, respectively. The waiting period for myclobutanil application was determined to be 12.41 days for the single dose and 25.58 days for the double dose, respectively. These waiting periods were based on the maximum residue limit of 0.6 ppm as prescribed by the Codex Alimentarius Commission, Food Safety and Standards Authority of India, and European Commission. The study concludes that myclobutanil 10 WP is safe for consumers at both recommended and double recommended doses when applied 2 months before harvest. Risk assessment, considering the average daily apple consumption in India and theoretical maximum residue contributions (TMRCs), indicates negligible health hazards even at double the recommended dosage. The calculated TMRC values at Day 0 were significantly below the maximum permissible intake. For average and maximum myclobutanil residues at single and double doses, the TMRC values were found to be 0.0069 and 0.0070 mg day−1 person−1 and 0.0105 and 0.0106 mg day−1 person−1, respectively. These results indicate that myclobutanil, when used according to recommended dosages and waiting periods, poses minimal health risks to consumers. The study emphasizes the importance of prudent fungicide use to minimize fungicide residues on fruits, thereby ensuring their safety for consumption.

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Myclobutanil enantioselective risk assessment in humans through in vitro CYP450 reactions: Metabolism and inhibition studies

Cited by 40 publications

References 37 publications

Prediction and Characterization of CYP3A4-mediated Metabolisms of Azole Fungicides: an Application of the Fused-grid Template* system

Prediction and Characterization of CYP3A4-mediated Metabolisms of Azole Fungicides: an Application of the Fused-grid Template* system

Effect of Myclobutanil Pesticide on the Physiological Behavior of Two Newly Isolated Saccharomyces cerevisiae Strains during Very-High-Gravity Alcoholic Fermentation

Residues determination, risk assessment, and dissipation behavior of myclobutanil formulation on apple

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