title: Impacts on Sirtuin Function and Bioavailability of the Dietary Bioactive Compound Dihydrocoumarin.
abstract: The plant secondary metabolite and common food additive dihydrocoumarin (DHC) is an inhibitor of the Sirtuin family of NAD+-dependent deacetylases. Sirtuins are key regulators of epigenetic processes that maintain silent chromatin in yeast and have been linked to gene expression, metabolism, apoptosis, tumorogenesis and age-related processes in multiple organisms, including humans. Here we report that exposure to the polyphenol DHC led to defects in several Sirtuin-regulated processes in budding yeast including the establishment and maintenance of Sir2p-dependent silencing by causing disassembly of silent chromatin, Hst1p-dependent repression of meiotic-specific genes during the mitotic cell cycle. As both transient and prolonged exposure to environmental and dietary factors have the potential to lead to heritable alterations in epigenetic states and to modulate additional Sirtuin-dependent phenotypes, we examined the bioavailability and digestive stability of DHC using an in vivo rat model and in vitro digestive simulator. Our analyses revealed that DHC was unstable during digestion and could be converted to melilotic acid (MA), which also caused epigenetic defects, albeit less efficiently. Upon ingestion, DHC was observed primarily in intestinal tissues, but did not accumulate over time and was readily cleared from the animals. MA displayed a wider tissue distribution and, in contrast to DHC, was also detected in the blood plasma, interstitial fluid, and urine, implying that the conversion of DHC to the less bioactive compound, MA, occurred efficiently in vivo.
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, United States of America.|Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Jacobi
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, United States of America.|Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Xu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Foods and Nutrition, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Menze
authors.affiliation: Department of Statistics, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Laurentz
authors.affiliation: Department of Foods and Nutrition, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Elsa M
authors.initials: EM
authors.lastname: Janle
authors.affiliation: Department of Food Science, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Mario G
authors.initials: MG
authors.lastname: Ferruzzi
authors.affiliation: Department of Statistics, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: George P
authors.initials: GP
authors.lastname: McCabe
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Clint
authors.initials: C
authors.lastname: Chapple
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, United States of America.|Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Kirchmaier
mesh_terms: D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D001682:Biological Availability; D003374:Coumarins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004032:Diet; D004063:Digestion; D045604:Extracellular Fluid / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D017930:Genes, Reporter; D056426:Genetic Loci; D009154:Mutation / Q000235:genetics; D010636:Phenols / Q000097:blood / Q000652:urine; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism*; D056565:Sirtuin 2 / Q000378:metabolism*; D013172:Spores, Fungal / Q000187:drug effects / Q000235:genetics; D034421:Sus scrofa
chemical_list: D003374:Coumarins; D010636:Phenols; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C030123:coumarin; C514152:melilotic acid; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; C026308:3,4-dihydrocoumarin