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Interaction of organophosphate pesticides and related compounds with the androgen receptor.
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MedLine Citation:
PMID:  12676613     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article    
Journal Detail:
Title:  Environmental health perspectives     Volume:  111     ISSN:  0091-6765     ISO Abbreviation:  Environ. Health Perspect.     Publication Date:  2003 Apr 
Date Detail:
Created Date:  2003-04-04     Completed Date:  2003-07-15     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0330411     Medline TA:  Environ Health Perspect     Country:  United States    
Other Details:
Languages:  eng     Pagination:  545-52     Citation Subset:  IM    
Department of Applied Biological Chemistry, Meijo University, Nagoya, Japan.
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MeSH Terms
Carcinoma, Hepatocellular / pathology
Drug Interactions
Fenitrothion / adverse effects*
Hydrogen Bonding
Insecticides / adverse effects*
Liver Neoplasms / pathology
Models, Molecular
Receptors, Androgen / drug effects*,  physiology*
Structure-Activity Relationship
Tumor Cells, Cultured
Reg. No./Substance:
0/Insecticides; 0/Receptors, Androgen; 122-14-5/Fenitrothion

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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Journal Information
Journal ID (nlm-ta): Environ Health Perspect
ISSN: 0091-6765
Article Information
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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.

Article Categories:
  • Research Article

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