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Interaction of organophosphate pesticides and related compounds with the androgen receptor.

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 organo...

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Autores principales: Tamura, Hiroto, Yoshikawa, Hiromichi, Gaido, Kevin W, Ross, Susan M, DeLisle, Robert K, Welsh, William J, Richard, Ann M
Formato: Texto
Lenguaje:English
Publicado: 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1241442/
https://www.ncbi.nlm.nih.gov/pubmed/12676613
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author Tamura, Hiroto
Yoshikawa, Hiromichi
Gaido, Kevin W
Ross, Susan M
DeLisle, Robert K
Welsh, William J
Richard, Ann M
author_facet Tamura, Hiroto
Yoshikawa, Hiromichi
Gaido, Kevin W
Ross, Susan M
DeLisle, Robert K
Welsh, William J
Richard, Ann M
author_sort Tamura, Hiroto
collection PubMed
description 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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spelling pubmed-12414422005-11-08 Interaction of organophosphate pesticides and related compounds with the androgen receptor. Tamura, Hiroto Yoshikawa, Hiromichi Gaido, Kevin W Ross, Susan M DeLisle, Robert K Welsh, William J Richard, Ann M Environ Health Perspect Research Article 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. 2003-04 /pmc/articles/PMC1241442/ /pubmed/12676613 Text en
spellingShingle Research Article
Tamura, Hiroto
Yoshikawa, Hiromichi
Gaido, Kevin W
Ross, Susan M
DeLisle, Robert K
Welsh, William J
Richard, Ann M
Interaction of organophosphate pesticides and related compounds with the androgen receptor.
title Interaction of organophosphate pesticides and related compounds with the androgen receptor.
title_full Interaction of organophosphate pesticides and related compounds with the androgen receptor.
title_fullStr Interaction of organophosphate pesticides and related compounds with the androgen receptor.
title_full_unstemmed Interaction of organophosphate pesticides and related compounds with the androgen receptor.
title_short Interaction of organophosphate pesticides and related compounds with the androgen receptor.
title_sort interaction of organophosphate pesticides and related compounds with the androgen receptor.
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1241442/
https://www.ncbi.nlm.nih.gov/pubmed/12676613
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