Metabolic Modulation of Estrogenicity of Endocrine Disrupting Chemicals by Cytochrome P450 in Human and Rat Livers
| Project/Area Number |
12672172
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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 |
Environmental pharmacy
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
YOSHIHARA Shin'ichi Faculty of Medicine, Hiroshima University, Associate Professor, 医学部, 助教授 (00037607)
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| Co-Investigator(Kenkyū-buntansha) |
YAMASAKI Kazuo Faculty of Medicine, Hiroshima University, Professor, 医学部, 教授 (00034017)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Endocrine disrupting chemicals / Estrogenicity / Xenobiotic metabolizing enzymes / Metabolic activation / Bisphenol A / Alkylphenols / Genistein / Biochanin A / 異物(薬物)代謝酵素 / ヒトP450 / ラット肝S9 / 内分泌撹乱化学物質 / オクチルフェノール |
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| Research Abstract |
Endocine disrupting chemicals (EDCs) are metabolized by xenobiotic metabolizing enzymes such as hepatic microsomal cytochrome P450 (P450). In order to make a precise risk assessment of estrogenic EDCs, metabolic modulation of their estrogenicity should be taken into account. Therefore, we investigated whether the incubation of estrogenic EDCs including soygean isoflavones such as genistein with human liver S9 and rat liver S9 or microsomes results in metabolic inactivation or activation of estrogenicity using a galactosidase reporter assay with recombinant yeast expressing human estrogen receptor. By incubation of 4-tert-octylphenol and 4-nonylphenol as well as genistein with rat liver S9, their estrogenic activities were metabolically inactivated. In contrast, the estrogenicity of bisphenol A (BPA) was increased several times by incubation with rat liver S9 as well as human liver S9 compared with those of the controls containing the inactivated S9. This metabolic activation of BPA required both microsomal and cytosolic fractions, indicating an involvement of another factor(s) in addition to P450. The structural feature of an active metabolite was tentatively suggested to be a dimer of isopropenyl phenol by LC/MS analysis. On the other hand, biochanin A, a weak estrogenic 4' -methoxy derivative of genistein, was predominantly converted to genistein, an active metabolite, with rat liver S9 or microsomes, resulting in an increase of estrogenicity. These results clearly demonstrated that the metabolic conversion of estrogenic EDCs catalyzed with xenobiotic metabolizing enzymes such as P450 caused a marked modulation of their estrogenicity.
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Report
(3 results)
Research Products
(8 results)
