The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases

Sirtuins are a family of phylogenetically conserved nicotinamide adenine dinucleotide-dependent deacetylases that have a firmly established role in aging. Using a simple Saccharomyces cerevisiae yeast heterochromatic derepression assay, we tested a number of environmental chemicals to address the po...

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Bibliographic Details
Published in:PLoS genetics 2005-12, Vol.1 (6), p.e77
Main Authors: Olaharski, Andrew J, Rine, Jasper, Marshall, Brett L, Babiarz, Joshua, Zhang, Luoping, Verdin, Eric, Smith, Martyn T
Format: Article
Language:English
Subjects:
Aging
Apoptosis
Cell culture
Cell Line, Tumor
Cellular Senescence
Coumarins - pharmacology
Cytotoxicity
Epigenesis, Genetic
Epigenetics
Experiments
Flavoring Agents - pharmacology
Fungal Proteins - chemistry
Gene Silencing
Genetics
Genetics/Epigenetics
Histone Deacetylase Inhibitors
Histone Deacetylases - genetics
Humans
In Vitro
Melilotus officinalis
Phenotype
Proteins
Ribosomal DNA
Saccharomyces
Saccharomyces cerevisiae
Silent Information Regulator Proteins, Saccharomyces cerevisiae - antagonists & inhibitors
Silent Information Regulator Proteins, Saccharomyces cerevisiae - genetics
Sirtuin 1
Sirtuin 2
Sirtuins - antagonists & inhibitors
Sirtuins - genetics
Toxicology - Environmental Health
Tumor Suppressor Protein p53 - metabolism
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Summary:Sirtuins are a family of phylogenetically conserved nicotinamide adenine dinucleotide-dependent deacetylases that have a firmly established role in aging. Using a simple Saccharomyces cerevisiae yeast heterochromatic derepression assay, we tested a number of environmental chemicals to address the possibility that humans are exposed to sirtuin inhibitors. Here we show that dihydrocoumarin (DHC), a compound found in Melilotus officinalis (sweet clover) that is commonly added to food and cosmetics, disrupted heterochromatic silencing and inhibited yeast Sir2p as well as human SIRT1 deacetylase activity. DHC exposure in the human TK6 lymphoblastoid cell line also caused concentration-dependent increases in p53 acetylation and cytotoxicity. Flow cytometric analysis to detect annexin V binding to phosphatidylserine demonstrated that DHC increased apoptosis more than 3-fold over controls. Thus, DHC inhibits both yeast Sir2p and human SIRT1 deacetylases and increases p53 acetylation and apoptosis, a phenotype associated with senescence and aging. These findings demonstrate that humans are potentially exposed to epigenetic toxicants that inhibit sirtuin deacetylases.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.0010077