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ToxSci Advance Access originally published online on February 18, 2003
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Toxicological Sciences 72, 57-65 (2003)
Copyright © 2003 by the Society of Toxicology

ENDOCRINE TOXICOLOGY

Acetaminophen Exhibits Weak Antiestrogenic Activity in Human Endometrial Adenocarcinoma (Ishikawa) Cells

Janet Dowdy*, Stacey Brower* and Michael R. Miller*,{dagger},{ddagger},1

* Department of Biochemistry and Molecular Pharmacology and {dagger} Mary Babb Randolph Cancer Center, West Virginia University Health Sciences Center, P.O. Box 9142, Morgantown, West Virginia 26506–9142; and {ddagger} National Institute of Occupational Safety and Health, Health Effects Laboratory Division, Morgantown, West Virginia 26505

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} and ß (ER{alpha} and ERß). Specifically, the extent to which acetaminophen altered the expression of estrogen-inducible alkaline phosphatase in endometrial adenocarcinoma (Ishikawa) cells and directly interacted with ERß and ER{alpha} was determined. Ishikawa cells were exposed to estradiol and/or to a range of concentrations of acetaminophen for four 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 ERß 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 antiestrogenic activity in Ishikawa cells without directly binding ER{alpha} or ERß.

Key Words: acetaminophen; Ishikawa cells; estrogen receptors; alkaline phosphatase; endocrine disruption.


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