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.
Highlights
Epigenetic processes controlling gene expression are influenced by both genetic and environmental factors
To investigate how DHC impacted Sir2p-dependent epigenetic processes, we monitored mating-type silencing in yeast in which a1-a2 at the silent mating-type locus HMR had been replaced with ADE2 or TRP1
Defects in maintaining or inheriting Sir2p-dependent silent chromatin were observed in the presence of 25 μM DHC relative to the absence of DHC, defects in establishing silencing were observed at 50 and 100 μM DHC and silencing was completely disrupted in 300 μM DHC (Fig 1A)
Summary
Epigenetic processes controlling gene expression are influenced by both genetic and environmental factors. Many natural compounds found in botanicals, and often used as dietary factors and food additives, have been identified that affect the activity of enzymes critical for establishing and maintaining epigenetic states. Such enzymes range from those regulating histone acetylation or methylation to DNA methylation ([1] and references within). As DHC is a potential dietary modulator of Sirtuin-dependent processes, in this study, we investigated a range of effects of DHC on yeast Sirtuin-dependent phenotypes as well as conducted detailed pharmacokinetics in Sprague Dawley rats of DHC’s absorption, tissue distribution, metabolism and excretion after ingestion
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