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

Carcinogenesis
Henry P CiolinoGrace Chao Yeh

Abstract

Sulindac, a widely used non-steroidal anti-inflammatory drug (NSAID), 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 (CYP) enzyme activity and in the expression of hepatic CYPs 1A1 and 1B1 mRNA. In the HepG2 human liver cancer cell line, sulindac caused a sustained, dose-dependent increase in CYP enzyme activity. Sulindac treatment resulted in a profound, dose-dependent increase in CYP 1A1 mRNA and a modest increase in 1A2 mRNA. The increase in CYP 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 (AhR), we examined the ability of sulindac to ac...Continue Reading

Citations

Nov 4, 2009·Proceedings of the National Academy of Sciences of the United States of America·Ian MoenchHerbert Weissbach
Mar 9, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·David BrunellHerbert Weissbach
Aug 11, 2012·The Journal of Pharmacology and Experimental Therapeutics·Un-Ho JinStephen Safe
Mar 12, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sara E BassGrace Chao Yeh
Sep 28, 2010·Biological Chemistry·Josef Abel, Thomas Haarmann-Stemmann
Feb 26, 2013·Journal of Clinical Pharmacology·Alexander K BergUNKNOWN Cancer Prevention Network
Nov 7, 2007·International Journal of Cancer. Journal International Du Cancer·Henry P CiolinoGrace Chao Yeh
Nov 14, 2019·Medicinal Research Reviews·Jennifer R BakerAdam McCluskey
Jan 8, 2021·Cellular & Molecular Immunology·Andreia BarrosoFrancisco J Quintana
Jul 18, 2015·Disease Models & Mechanisms·Dessislava N MladenovaMaija R J Kohonen-Corish

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