Carcinogenesis Advance Access published online on August 4, 2005
Carcinogenesis, doi:10.1093/carcin/bgi206
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1 Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208 (USA)
* To whom correspondence should be addressed. We studied the modulating effects of caffeic acid and chlorogenic acid (two common coffee polyphenols) on the in vitro methylation of synthetic DNA substrates and also on the methylation status of the promoter region of a representative gene in cultured cells. Under conditions that were suitable for the in vitro enzymatic methylation of DNA and dietary catechols, we found the presence of caffeic acid or chlorogenic acid inhibited in a concentration-dependent manner DNA methylation catalyzed by prokaryotic M.SssI DNA methyltransferase (DNMT) and human DNMT1. The IC50 values of caffeic acid and chlorogenic acid were 3.0 and 0.75 (M, respectively, for inhibition of M.SssI DNMT-mediated DNA methylation, and were 2.3 and 0.9 µM, respectively, for inhibition of human DNMT1-mediated DNA methylation. The maximal in vitro inhibition of DNA methylation was
Received June 2, 2005
Revised July 29, 2005
Accepted July 29, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols
Bao Ting Zhu, E-mail: BTZhu{at}cop.sc.edu
Abstract 
80% when the highest concentration (20 µM) of caffeic acid or chlorogenic acid was tested. Kinetic analyses showed that DNA methylation catalyzed by M.SssI DNMT or human DNMT1 followed the Michaelis-Menten curve patterns. The presence of caffeic acid or chlorogenic acid inhibited DNA methylation predominantly through a noncompetitive mechanism, and this inhibition was largely due to increased formation of S-adenosyl-L-homocysteine (SAH, a potent inhibitor of DNA methylation), resulting from the catechol-O-methyltransferase (COMT)-mediated O-methylation of these dietary catechols. Using cultured MCF-7 and MAD-MB-231 human breast cancer cells, we also demonstrated that treatment of these cells with caffeic acid or chlorogenic acid partially inhibited the methylation status of the promoter region of RAR
gene. The findings of our present study provide a general mechanistic basis for the notion that a variety of dietary catechols can function as inhibitors of DNA methylation through increased formation of SAH during the COMT-mediated O-methylation of these dietary chemicals.
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