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Carcinogenesis Advance Access published online on March 10, 2006
Carcinogenesis, doi:10.1093/carcin/bgi359
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Published by Oxford University Press 2006
Received October 28, 2005
Revised January 5, 2006
Accepted January 27, 2006

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Sulindac regulates the aryl hydrocarbon receptor-mediated expression of Phase 1 metabolic enzymes in vivo and in vitro

Henry P. Ciolino 1 *, Christopher J. MacDonald 1, Omar S. Memon 1, Sara E. Bass 1, and Grace Chao Yeh 1

1 Cellular Defense and Carcinogenesis Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD, USA 21702-1201

* To whom correspondence should be addressed.
Henry P. Ciolino, E-mail: hciolino{at}ncifcrf.gov


  Abstract

Sulindac, a widely used non-steroidal anti-inflammatory drug, has been shown to inhibit chemically-induced carcinogenesis in animal models. In the present study we have investigated the molecular mechanism by which sulindac affects the activity and expression of the enzymes that mediate the initial detoxification steps of many environmental carcinogens, the cytochromes P450 1A1, 1A2, and 1B1. Sulindac treatment of Sprague-Dawley rats resulted in a dose-dependent increase in hepatic cytochrome P450 enzyme activity and in the expression of hepatic cytochromes P450 1A1 and 1B1 mRNA. In the HepG2 human liver cancer cell line, sulindac caused a sustained, dose-dependent increase in cytochrome P450 enzyme activity. Sulindac treatment resulted in a profound, dose-dependent increase in cytochrome P450 1A1 mRNA, and a modest increase in 1A2 mRNA. The increase in cytochrome P450 1A1 mRNA induced by sulindac was, like enzyme activity, sustained for several days after the initial treatment. Sulindac induced the transcription of the CYP1A1 gene, as measured by the level of heterogeneous nuclear 1A1 RNA and by actinomycin D chase experiment. Since the transcription of CYP1A1 is under the control of the aryl hydrocarbon receptor, we examined the ability of sulindac to activate the receptor. Sulindac bound to the aryl hydrocarbon receptor, as measured by ligand-binding assay, and induced the binding of the aryl hydrocarbon receptor with the xenobiotic responsive element present in the promoter region of the CYP1A1 gene. These results are the first demonstration that non-steroidal anti-inflammatory drugs modulate carcinogen metabolic enzymes, and provide a novel mechanism to explain the established chemopreventive activity of sulindac.


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