Prediction of behavior of endocrine disruptors and their metabolites in human bodies
| Project/Area Number |
16510158
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Living organism molecular science
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| Research Institution | Kyoto University |
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Principal Investigator |
AKAMATSU Miki Kyoto University, Agriculture, Associate Professor, 農学研究科, 助教授 (70183134)
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| Co-Investigator(Kenkyū-buntansha) |
MIYASHITA Masahiro Kyoto University, Agriculture, Assistant Professor, 農学研究科, 助手 (80324664)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | endocrine disruptors / metabolites / artificial membrane permeability / P-gp / quantitative structure-activity relationships / pesticides / ABC transporter / chemicals behavior in humans |
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| Research Abstract |
To evaluate absorption of chemical compounds including endocrine disruptors and agrochemicals across a membrane via the transcellular route, their permeability was measured using the parallel artificial membrane permeation assay (PAMPA). The permeability coefficients by PAMPA were analyzed using classical quantitative structure-activity relationship (QSAR) approach with simple physicochemical parameters. We formulated correlation equations for structurally diverse chemicals similar to the equation obtained for peptide-related compounds in our previous study. The hydrogen bonding ability of molecules, not only hydrogen-accepting ability but also hydrogen-donating ability, in addition to hydrophobicity at a particular pH, was significant in determining variations in PAMPA permeability coefficients. Based on this result, an in silico good prediction model for the passive transcellular permeability of diverse structural compounds was obtained. The artificial lipid-membrane permeability coefficients of the compound were well correlated with the Caco-2 permeability, suggesting the importance of absorption by the transcellular mechanism.
Efflux is also important for evaluation of absorption of chemical compounds which are suspected as endocrine disruptors. P-glycoprotein(P-gp) is a member of the ATP-binding cassette (ABC) transporter superfamily and plays an important role for efflux of xenobiotics and multidrug resistance in human bodies. However, details of QSAR of P-gp substrates is still unclear. Using human P-gp expressed in insect cells, ATPase activity of P-gp of a variety of compounds such as agrochemicals, peptide derivatives was measured to investigate whether they can be substrates of P-gp. Several agrochemicals and peptide derivatives had the ATPase activity, showing the possibility of the compounds as substrates.
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Report
(3 results)
Research Products
(3 results)
