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Androgen receptor antagonism by the organophosphate insecticide fenitrothion.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Tamura, Hideyuki Maness, Susan C. Reischmann, Kim P. Dorman, David Gray, Leon Earl Gaido, Kevin W. |
| Copyright Year | 2001 |
| Abstract | Organophosphate insecticides represent one of the most widely used classes of pesticides with high potential for human exposure in both rural and residential environments. We investigated the interaction of the organophosphothioate pesticide fenitrothion (O,O-dimethyl O-(4-nitro-m-tolyl) phosphorothioate) with the human androgen receptor (AR). Fenitrothion blocked dihydrotestosterone-dependent AR activity in a concentration-dependent and competitive manner in HepG2 human hepatoma liver cells transiently transfected with human AR and an AR-dependent luciferase reporter gene. Schild regression analysis yielded an equilibrium dissociation constant value of 2.18 x 10(-8) M. To determine the antiandrogenic potential of fenitrothion in vivo, 7-week-old castrated Sprague-Dawley rats were dosed once a day for 7 days with testosterone propionate (50 microg/day, sc) plus gavage doses of either corn oil vehicle or fenitrothion (15 or 30 mg/kg/day). An additional group of rats was given testosterone propionate and flutamide (50 mg/kg/day). Motor activity and acetylcholinesterase activity in whole blood and brain were also assessed. Both fenitrothion and the reference antiandrogen flutamide caused significant decreases in the ventral prostate, seminal vesicle, and levator ani plus bulbocavernosus muscles tissue weights. In contrast, blood acetylcholinesterase activity, a standard biomarker of organophosphate poisoning, was only inhibited at the higher dose of fenitrothion (30 mg/kg). Our results demonstrate that fenitrothion is a competitive AR antagonist, comparable in potency to the pharmaceutical antiandrogen flutamide and more potent, based on in vitro assays, than the known environmental antiandrogens linuron and p,p'-, 2,2-bis(p-hydroxyphenyl)-1,1-dichloroethylene ( p,p'-DDE). |
| Starting Page | 56 |
| Ending Page | 62 |
| Page Count | 7 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/toxsci/60/1/10.1093_toxsci_60.1.56/1/060056.pdf?Expires=1492489712&Key-Pair-Id=APKAIUCZBIA4LVPAVW3Q&Signature=GiRV34I-zKrW0VUl4S99rY0sPCla1Sczn2IZmMmHTqmfanWExFudaOswbIptjYvj3QBNSHJG3TAomE738bDdK3qJMn9qzwVZTKiTb5S6OcLDd4TDsFsGaf9k9rpcndbBDUdt1KsOinVdLD2hdXQnx79ZZqwfKPAUpvFnMr~m4ouKCMMVeGFfQkAxkYBqzdf8PxFIc~ykIYKM-Jhd~1Ez6lK6THAsaJnkK3~LHlPhLSY5Mthf8JvvHWslRRYQLwddb9n6cdZo~3YhM3TizHmT36vK0znf~77mlrFiFqjLpJ8hpdKCqjUiPgaLSyt4xaDslHUh9~dePB7rGMI20HrDZw__ |
| PubMed reference number | 11222873v1 |
| Volume Number | 60 |
| Issue Number | 1 |
| Journal | Toxicological sciences : an official journal of the Society of Toxicology |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | AR protein, human Androgen Antagonists Androgens Biological Markers Class Corn Oil Dichlorodiphenyl Dichloroethylene Dihydrotestosterone Dimethyl Adipimidate Fenitrothion Flutamide Hepatocyte Insecticides Linuron Liver carcinoma Luciferases Milligram per Kilogram per Day Organophosphate poisoning Organophosphates Pesticides Seminal Vesicles Structure of bulbospongiosus muscle Structure of levator ani muscle Testosterone Propionate Tube feeding of patient Vesicle (morphologic abnormality) Weight acetylcholinesterase activity mg/kg phosphorothioate |
| Content Type | Text |
| Resource Type | Article |
