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First published on August 24, 2005; DOI: 10.1124/dmd.105.006502

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Received for publication July 12, 2005.
Revised August 22, 2005.
Accepted for publication August 23, 2005.

Modulation of human cytochrome P450 1B1 expression by 2,4,3',5'- tetramethoxystilbene

Young-Jin Chun 1*, Sang Kwang Lee 2, Mie Young Kim 3

1 College of Pharmacy, Chung-Ang University 2 College of Pharmacy, Chung-Ang University, Seoul, Korea 3 College of Pharmacy, Chung-Ang University, Seoul,Korea

* Address correspondence to: E-mail: moltox{at}hanafos.com

Abstract

We have previously shown that 2,4,3' ,5'-tetramethoxystilbene (TMS), a synthetic trans-stilbene analogue, is one of the most potently selective inhibitors of recombinant human cytochrome P450 (CYP) 1B1 in vitro. In the present studies, the effects of TMS on CYP1B1 expression were investigated in human cancer cells. TMS significantly inhibited CYP1-mediated 7-ethoxyresorufin O-deethylation (EROD) activity in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced MCF-7 cells or lung microsomes of Sprague Dawley rats treated with 7,12-dimethylbenz[a]anthracene (DMBA). TCDD-stimulated CYP1B1 protein and mRNA expression were significantly suppressed by TMS in a concentration-dependent manner in MCF-7, MCF-10A, and HL- 60 cells. While TMS down-regulated TCDD-induced CYP1B1 gene expression, the levels of AhR and ARNT mRNA expression were not changed by TMS treatment. In human cancer cells, TMS induced apoptotic cell death and the cytotoxic effects of TMS were significant when the cells were incubated with TCDD. CYP1B1 was able to convert TMS to a metabolite(s) when incubated with NADPH. Metabolic activation of TMS by CYP1B1 induced by TCDD may mediate cellular toxicity of TMS in human cancer cells because the sensitivity to TMS in MCF-7 cells treated with TCDD were more significant than in HL-60 cells treated with TCDD. Taken together, our results indicate that TMS acts as a strong modulator of CYP1B1 gene expression as well as a potent selective inhibitor in vitro. The ability of TMS to induce apoptotic cell death in tumor cells, as well as CYP1B1 inhibition, may contribute to its usefulness for cancer chemoprevention.


Key words: apoptosis, CYP1B, enzyme inhibitors, human CYP enzymes, molecular drug targeting


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H. Park, S. E. Aiyar, P. Fan, J. Wang, W. Yue, T. Okouneva, C. Cox, M. A. Jordan, L. Demers, H. Cho, et al.
Effects of Tetramethoxystilbene on Hormone-Resistant Breast Cancer Cells: Biological and Biochemical Mechanisms of Action
Cancer Res., June 15, 2007; 67(12): 5717 - 5726.
[Abstract] [Full Text] [PDF]


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