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 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.
Olaharski
Andrew J
AJ
School of Public Health, University of California Berkeley, Berkeley, California, USA. drewski@berkeley.edu
Rine
Jasper
J
Marshall
Brett L
BL
Babiarz
Joshua
J
Zhang
Luoping
L
Verdin
Eric
E
Smith
Martyn T
MT
D000375:Aging; D017209:Apoptosis; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D003374:Coumarins / Q000494:pharmacology*; D044127:Epigenesis, Genetic; D005421:Flavoring Agents / Q000494:pharmacology*; D005656:Fungal Proteins / Q000737:chemistry; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D010641:Phenotype; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000037:antagonists & inhibitors / Q000235:genetics; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D003374:Coumarins; D005421:Flavoring Agents; D005656:Fungal Proteins; D056572:Histone Deacetylase Inhibitors; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D016159:Tumor Suppressor Protein p53; C087778:SIR2 protein, S cerevisiae; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases; C026308:3,4-dihydrocoumarin