In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans
Abstract
:1. Introduction
2. Materials and Methods
2.1. Pesticide Selection
2.2. In Silico Evaluation of Intestine and Brain Permeation
2.3. Association of Pesticide Physicochemical Parameters and Predicted Permeation across Intestinal or Blood-Brain Barriers
2.4. Confrontation of Predicted and Measured Human Intestinal Absorption Values for Some Pesticides
3. Results
3.1. Prediction of Intestinal and Brain Permeation of Pesticides
3.2. Pesticide Physicochemical Parameters Associated with the Prediction of Intestinal or Brain Permeation
3.3. Confrontation of Predicted and Measured Human Intestinal Absorption for Some Pesticides
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Conflicts of Interest
Appendix A
References
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Organophosphorus Pesticide | Brain Permeation Prediction | |
---|---|---|
Parent Molecule | Oxon Metabolite | |
Bensulide | No | No |
Chlorpyrifos | No | Yes |
Chlorpyrifos-methyl | No | Yes |
Coumaphos | No | No |
Diazinon | No | No |
Ethion | No | No |
Fenthion | No | No |
Fonofos | No | Yes |
Malathion | No | No |
Methyl-parathion | No | No |
Parathion | No | No |
Phorate | No | No |
Phosmet | No | No |
Sulprofos | No | No |
Terbufos | No | No |
Physicochemical Parameter | Parameter Value (Mean ± SD) | ||
---|---|---|---|
Low Intestinal Absorption (n = 63 Pesticides) | High Intestinal Absorption (n = 275 Pesticides) | Significance 2 | |
Molecular weight (g/mol) | 420.4 ± 145.4 | 284.0 ± 79.3 | S (p < 0.0001) |
Mean atomic van der Waals volume | 0.7 ± 0.1 | 0.6 ± 0.1 | S (p < 0.0001) |
Mean atomic polarizability | 0.8 ± 0.5 | 0.7 ± 0.1 | S (p < 0.0001) |
Number of heavy atoms | 24.2 ± 11.4 | 18.0 ± 5.3 | S (p < 0.0001) |
Number of aromatic heavy carbons | 6.6 ± 6.3 | 5.5 ± 4.4 | NS (p = 0.1050) |
Fraction Csp3 | 0.5 ± 0.3 | 0.5 ±0.3 | NS (p = 0.7335) |
Number of rotatable bonds | 6.2 ± 4.2 | 5.4 ± 2.2 | S (p = 0.0252) |
Number of H-bond acceptors | 4.5 ± 4.3 | 3.5 ± 1.6 | S (p = 0.0031) |
Number of H-bond donors | 0.4 ± 0.9 | 0.6 ± 0.8 | NS (p = 0.0550) |
LogS (Silicos-IT) | −6.0 ± 2.5 | −3.8 ± 1.9 | S (p < 0.0001) |
XLogP3 | 5.2 ± 2.1 | 3.1 ± 1.8 | S (p < 0.0001) |
Molar refractivity | 97.4 ± 37.6 | 73.2 ± 19.9 | S (p < 0.0001) |
tPSA (Å2) | 68.1 ± 61.3 | 70.3 ± 27.7 | NS (p = 0.6675) |
Physicochemical Parameter | Parameter Value (Mean ± SD) | ||
---|---|---|---|
No-Brain Permeation (n = 208 Pesticides) | Brain Permeation (n = 130 Pesticides) | Significance 2 | |
Molecular weight (g/mol) | 332.2 ± 120.2 | 273.1 ± 74.6 | S (p < 0.0001) |
Mean atomic van der Waals volume | 0.7 ± 0.1 | 0.6 ± 0.1 | S (p = 0.0225) |
Mean atomic polarizability | 0.7 ± 0.3 | 0.7 ± 0.1 | NS (p = 0.0510) |
Number of heavy atoms | 20.0 ± 8.3 | 17.8 ± 4.8 | S (p = 0.0061) |
Number of aromatic heavy carbons | 5.9 ± 5.2 | 5.4 ± 4.2 | NS (p = 0.3634) |
Fraction Csp3 | 0.5 ± 0.3 | 0.5 ± 0.3 | NS (p = 0.4746) |
Number of rotatable bonds | 6.0 ± 2.9 | 4.8 ± 2.2 | S (p < 0.0001) |
Number of H-bond acceptors | 4.3 ± 2.7 | 2.8 ± 1.3 | S (p < 0.0001) |
Number of H-bond donors | 0.6 ± 0.9 | 0.6 ± 0.7 | NS (p = 0.6422) |
LogS (Silicos-IT) | −4.2 ± 2.5 | −4.1 ± 1.6 | NS (p = 0.6153) |
XLogP3 | 3.6 ± 2.4 | 3.4 ± 1.4 | NS (p = 0.4395) |
Molar refractivity | 81.1 ± 29.1 | 72.2 ± 18.4 | S (p = 0.0021) |
tPSA (Å2) | 83.3 ± 39.2 | 48.5 ± 15.2 | S (p < 0.0001) |
Number of N and O atoms | 4.4 ± 2.5 | 3.4 ± 1.2 | S (p < 0.0001) |
Pesticide | Class | Intestinal Absorption 1 | |
---|---|---|---|
Determined from Pharmacokinetics Studies | Predicted by SwissADME Webtool | ||
Cypermethrin | Pyrethroid | High (Fa = 0.40 [40,41]) | High |
Deltamethrin | Pyrethroid | High (Fa > 0.48 [42,43]) | High |
Permethrin | Pyrethroid | High (Fa ≥ 0.32 [44]) | High |
Bendiocarb | Carbamate | High (Fa ≥ 0.99 [45]) | High |
Pirimicarb | Carbamate | High (Fa = 0.74 [46]) | High |
Molinate | Carbamate | High (Fa > 0.40 [22]) | High |
Propoxur | Carbamate | High (Fa > 0.37 [47,48]) | High |
DDT 2 | Organochlorine | Low (Fa = 0.15 [49]) | Low |
Pentachlorophenol | Organochlorine | High (Fa > 0.86 [50]) | High |
TCDD 2 | Organochlorine | High (Fa > 0.87 [51]) | Low |
Chlorpyrifos | Organophosphorus compound | High (Fa = 0.82 [52,53]) | High |
Diazinon | Organosphosphorus compund | High (Fa > 0.66 [54]) | High |
Dichlorvos | Organophosphorus compound | High (Fa > 0.36 [55]) | High |
Dimethoate | Organosphosphorus compound | High (Fa = 0.86 [56,57]) | High |
Fenitrothion | Organophosphorus compound | High (Fa = 0.81 [58]) | High |
Parathion | Organophosphorus compound | High (Fa > 0.46 [59]) | High |
Propetamphos | Organophosphorus compound | High (Fa > 0.41 [60]) | High |
2,4,5-T 2 | Miscellaneous | High (Fa > 0.89 [61]) | High |
2,4-D 2 | Miscellaneous | High (Fa = 0.85 [62,63]) | High |
Fluazifop-butyl | Miscellaneous | High (Fa = 0.88 [64]) | High |
MCPA 2 | Miscellaneous | High (Fa > 0.55 [65]) | High |
Paraquat | Miscellaneous | Low (Fa ≤ 0.05 [66]) | Low |
Picloram | Miscellaneous | High (Fa = 0.91 [67]) | High |
Triclopyr | Miscellaneous | High (Fa > 0.82 [68]) | High |
Warfarine | Miscellaneous | High (Fa > 0.93 [69]) | High |
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Chedik, L.; Mias-Lucquin, D.; Bruyere, A.; Fardel, O. In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans. Int. J. Environ. Res. Public Health 2017, 14, 708. https://doi.org/10.3390/ijerph14070708
Chedik L, Mias-Lucquin D, Bruyere A, Fardel O. In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans. International Journal of Environmental Research and Public Health. 2017; 14(7):708. https://doi.org/10.3390/ijerph14070708
Chicago/Turabian StyleChedik, Lisa, Dominique Mias-Lucquin, Arnaud Bruyere, and Olivier Fardel. 2017. "In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans" International Journal of Environmental Research and Public Health 14, no. 7: 708. https://doi.org/10.3390/ijerph14070708