| Interaction of organophosphate pesticides and related compounds with the androgen receptor. | |
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MedLine Citation:
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PMID: 12676613 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Identification of several environmental chemicals capable of binding to the androgen receptor (AR) and interfering with its normal function has heightened concern about adverse effects across a broad spectrum of environmental chemicals. We previously demonstrated AR antagonist activity of the organophosphate (OP) pesticide fenitrothion. In this study, we characterized AR activity of analogues of fenitrothion to probe the structural requirements for AR activity among related chemicals. AR activity was measured using HepG2 human hepatoma cells transfected with human AR plus an androgen-responsive luciferase reporter gene, MMTV-luc. AR antagonist activity decreased as alkyl chain length of the phosphoester increased, whereas electron-donating properties of phenyl substituents of the tested compounds did not influence AR activity. Oxon derivatives of fenitrothion, which are more likely to undergo hydrolytic degradation, had no detectable AR antagonist activity. Molecular modeling results suggest that hydrogen-bond energies and the maximum achievable interatomic distance between two terminal H-bond capable sites may influence both the potential to interact with the AR and the nature of the interaction (agonist vs. antagonist) within this series of chemicals. This hypothesis is supported by the results of recent AR homology modeling and crystallographic studies relative to agonist- and antagonist-bound AR complexes. The present results are placed in the context of structure-activity knowledge derived from previous modeling studies as well as studies aimed toward designing nonsteroidal antiandrogen pharmaceuticals. Present results extend understanding of the structural requirements for AR activity to a new class of nonsteroidal, environmental, OP-related chemicals. |
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Authors:
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Hiroto Tamura; Hiromichi Yoshikawa; Kevin W Gaido; Susan M Ross; Robert K DeLisle; William J Welsh; Ann M Richard |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Environmental health perspectives Volume: 111 ISSN: 0091-6765 ISO Abbreviation: Environ. Health Perspect. Publication Date: 2003 Apr |
Date Detail:
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Created Date: 2003-04-04 Completed Date: 2003-07-15 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 0330411 Medline TA: Environ Health Perspect Country: United States |
Other Details:
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Languages: eng Pagination: 545-52 Citation Subset: IM |
Affiliation:
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Department of Applied Biological Chemistry, Meijo University, Nagoya, Japan. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Carcinoma, Hepatocellular
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pathology Drug Interactions Fenitrothion / adverse effects* Humans Hydrogen Bonding Insecticides / adverse effects* Liver Neoplasms / pathology Models, Molecular Receptors, Androgen / drug effects*, physiology* Structure-Activity Relationship Transfection Tumor Cells, Cultured |
| Chemical | |
Reg. No./Substance:
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0/Insecticides; 0/Receptors, Androgen; 122-14-5/Fenitrothion |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
| Full Text | |
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Journal Information Journal ID (nlm-ta): Environ Health Perspect ISSN: 0091-6765 |
Article Information Download PDF  Print publication date: Month: 4 Year: 2003 Volume: 111 Issue: 4 First Page: 545 Last Page: 552 ID: 1241442 PubMed Id: 12676613 |
| Interaction of organophosphate pesticides and related compounds with the androgen receptor. | |
| Hiroto Tamura | |
| Hiromichi Yoshikawa | |
| Kevin W Gaido | |
| Susan M Ross | |
| Robert K DeLisle | |
| William J Welsh | |
| Ann M Richard | |
| Department of Applied Biological Chemistry, Meijo University, Nagoya, Japan. |
|
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