| Flavonoids as Aryl Hydrocarbon Receptor Agonists/Antagonists: Effects of Structure and Cell Context Shu Zhang,1 Chunhua Qin,1 and Stephen H. Safe1,2
1Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA; 2Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas, USA Abstract
Chemoprotective phytochemicals exhibit multiple activities and interact with several cellular receptors, including the aryl hydrocarbon (Ah) receptor (AhR) . In this study we investigated the AhR agonist/antagonist activities of the following flavonoids: chrysin, phloretin, kaempferol, galangin, naringenin, genistein, quercetin, myricetin, luteolin, baicalein, daidzein, apigenin, and diosmin. We also investigated the AhR-dependent activities of cantharidin and emodin (in herbal extracts) in Ah-responsive MCF-7 human breast cells, HepG2 human liver cancer cells, and mouse Hepa-1 cells transiently or stably transfected with plasmids expressing a luciferase reporter gene linked to multiple copies of a consensus dioxin-responsive element. The AhR agonist activities of the compounds (1 and 10 µM) were as high as 25% of the maximal response induced by 5 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) , and their potencies were dependent on cell context. Galangin, genistein, daidzein, and diosmin were active only in Hepa-1 cells, and cantharidin induced activity only in human HepG2 and MCF-7 cells. Western blot analysis confirmed that baicalein and emodin also induced CYP1A1 protein in the human cancer cell lines. The AhR antagonist activities of four compounds inactive as agonists in MCF-7 and HepG2 cells (kaempferol, quercetin, myricetin, and luteolin) were also investigated. Luteolin was an AhR antagonist in both cell lines, and the inhibitory effects of the other compound were dependent on cell context. These data suggest that dietary phytochemicals exhibit substantial cell context-dependent AhR agonist as well as antagonist activities. Moreover, because phytochemicals and other AhR-active compounds in food are present in the diet at relatively high concentrations, risk assessment of dietary toxic equivalents of TCDD and related compounds should also take into account AhR agonist/antagonist activities of phytochemicals. Key words: agonists, Ah receptor, antagonists, flavonoids, interactions, TCDD. Environ Health Perspect 111:1877-1882 (2003) . doi:14644660 available via http://dx.doi.org/ [Online 22 August 2003]
Address correspondence to S.H. Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466 USA. Telephone: (979) 845-5988. Fax: (979) 862-4929. E-mail: ssafe@cvm.tamu.edu This study received support from the Research Foundation for Health and Environmental Effects, the National Institutes of Health (grants ES09106 and ES04917) , and the Texas Agricultural Experiment Station. The authors declare they have no competing financial interests. Received 6 March 2003 ; accepted 21 August 2003.
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