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Journal Article 
The Flavoring Agent Dihydrocoumarin Is An Epigenetic Toxicant That Inhibits Sirtuin Deacetylases 
Olaharski, AJ; Rine, J; Marshall, B; Babiarz, J; Zhang, L; Verdin, E; Smith, MT 
Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 
Epigenetic drift is hypothesized to occur, in part, through exposure to environmental and dietary compounds that affect the processes responsible for the proper maintenance of the proteome and epigenome (Jaenisch and Bird, 2003). The recent discovery that sirtuin deacetylase activity could be enhanced by the red wine component resveratrol (Howitz et al., 2004), suggested that the diet and environment might also contain epigenetic toxicants that inhibit sirtuin enzymes. We tested a number of environmental chemicals using a Saccharomyces cerevisiae yeast heterochromatic de-repression mating assay to address the possibility that humans are exposed to sirtuin inhibitors and epigenetic toxicants. We have screened over 300 environmental chemicals to date, including benzene and its metabolites, sodium arsenite, psoralen, etoposide, as well as a number of commonly used pesticides, all of which tested negative in the assay. Dihydrocoumarin (DHC), a common flavoring agent and constituent of cosmetics, tested positive and was identified to reverse heterochromatic silencing at levels similar to splitomicin, an established Sir2p inhibitor. Additional experiments demonstrated that the addition of 750 uM DHC reversed the lethal phenotype of a SIR2 over-expressing plasmid, thus pinpointing Sir2p as the direct target of DHC-mediated heterochromatic de-repression. Further analyses demonstrated that DHC inhibited both the SIRT1 and SIRT2 human sirtuin deacetylases in a dose-dependent manner (IC50 of 208 and 295 uM, respectively). We exposed the human TK6 lymphoblastoid cell line with DHC to test whether DHC could reverse SIRT1-mediated negative regulation of p53. Concentration-dependent increases in p53 acetylation as well as apoptosis were observed suggesting that human exposure to DHC may elicit negative effects. Current studies are addressing the potential impacts that DHC-mediated sirtuin deacetylase inhibition may have upon epigenetic drift and human health. 
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