PT  - JOURNAL ARTICLE
AU  - Young-Jin Chun
AU  - Sang-Kwang Lee
AU  - Mie Young Kim
TI  - MODULATION OF HUMAN CYTOCHROME P450 1B1 EXPRESSION BY 2,4,3′,5′-TETRAMETHOXYSTILBENE
AID  - 10.1124/dmd.105.006502
DP  - 2005 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1771--1776
VI  - 33
IP  - 12
4099  - http://dmd.aspetjournals.org/content/33/12/1771.short
4100  - http://dmd.aspetjournals.org/content/33/12/1771.full
SO  - Drug Metab Dispos2005 Dec 01; 33
AB  - We have previously shown that 2,4,3′,5′-tetramethoxystilbene (TMS), a synthetic trans-stilbene analog, is one of the most potently selective inhibitors of recombinant human cytochrome P450 1B1 (CYP1B1) 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 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. TCDD-stimulated CYP1B1 protein and mRNA expression was significantly suppressed by TMS in a concentration-dependent manner in MCF-7, MCF-10A, and HL-60 cells. Whereas TMS down-regulated TCDD-induced CYP1B1 gene expression, the levels of aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator 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 was 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. The American Society for Pharmacology and Experimental Therapeutics