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ToxSci Advance Access published online on February 18, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg005
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received September 3, 2002; accepted November 27, 2002
© 2003 Society of Toxicology

Endocrine Toxicology

Acetaminophen Exhibits Weak Anti-Estrogenic Activity in Human Endometrial Adenocarcinoma (Ishikawa) Cells

Janet Dowdy 1, Stacey Brower 1, Michael R. Miller 2*

1 Department of Biochemistry & Molecular Pharmacology, West Virginia University Health Sciences Center, PO Box 9142, Morgantown, WV 26506-9142
2 Department of Biochemistry & Molecular Pharmacology, West Virginia University Health Sciences Center, PO Box 9142, Morgantown, WV 26506-9142; Mary Babb Randolph Cancer Center, West Virginia University Health Sciences Center, PO Box 9142, Morgantown, WV 26506-9142; NIOSH, Health Effects Laboratory Division, Morgantown, WV 26505

* To whom correspondence should be addressed. E-mail: mmiller{at}hsc.wvu.edu.


  Abstract

The purpose of this study was to test the hypothesis that acetaminophen would alter an estrogen-regulated process in human cells that express endogenous estrogen receptor {alpha} (ER{alpha}) and ER{beta}. Specifically, the extent to which acetaminophen altered the expression of estrogen-inducible alkaline phosphatase in endometrial adenocarcinoma (Ishikawa) cells and directly interacted with ER{beta} and ER{alpha} was determined. Ishikawa cells were exposed to estradiol and/or to a range of concentrations of acetaminophen for 4 days, and alkaline phosphatase activity was measured spectrophotometrically. Acetaminophen inhibited both basal and estradiol-induced alkaline phosphatase activity in Ishikawa cells in a concentration-dependent manner. The reduction of Ishikawa cell alkaline phosphatase was not due to direct inhibition of enzyme activity by acetaminophen. Toxic effects of acetaminophen on Ishikawa cells were determined by measuring loss of cellular lactate dehydrogenase to culture medium. High concentrations of acetaminophen (>= 0.5 mM) induced lactate dehydrogenase release from cells and reduced the amount of cellular protein in culture dishes, indicating some acetaminophen-induced reduction of alkaline phosphatase activity might be attributed to toxic effects. However, lower concentrations of acetaminophen significantly reduced alkaline phosphatase activity in the absence of detectable toxicity. Acetaminophen also augmented 4-hydroxy-tamoxifen reduction of alkaline phosphatase activity. Competition binding assays with human ER{alpha} and ER{beta} demonstrated 106-fold molar excess acetaminophen did not directly interact significantly with the ligand-binding domain of either receptor. These studies indicate acetaminophen exerts weak anti-estrogenic activity in Ishikawa cells without directly binding ER{alpha} or ER{beta}.

acetaminophen, Ishikawa cells, estrogen receptors, alkaline phosphatase, endocrine disruption .


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