Flavonoids are polyphenolic secondary metabolites synthesized by plants and fungus with various pharmacological effects. Due to their plethora of biological activities, they have been studied extensively in drug development. They have been shown to modulate the activity of a NAD+-dependent histone deacetylase, SIRT6. Because SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction, it is an interesting target in inflammatory and metabolic diseases as well as in cancer. Here we show, that flavonoids can alter SIRT6 activity in a structure dependent manner. Catechin derivatives with galloyl moiety displayed significant inhibition potency against SIRT6 at 10 µM concentration. The most potent SIRT6 activator, cyanidin, belonged to anthocyanidins, and produced a 55-fold increase in SIRT6 activity compared to the 3–10 fold increase for the others. Cyanidin also significantly increased SIRT6 expression in Caco-2 cells. Results from the docking studies indicated possible binding sites for the inhibitors and activators. Inhibitors likely bind in a manner that could disturb NAD+ binding. The putative activator binding site was found next to a loop near the acetylated peptide substrate binding site. In some cases, the activators changed the conformation of this loop suggesting that it may play a role in SIRT6 activation.

The human CYP2A gene subfamily consists of three members, CYP2A6, CYP2A7, and CYP2A13. The CYP2A6 gene is highly polymorphic with approximately 40 annotated allelic variants. Individuals homozygous for some of these alleles have a total lack of CYP2A6 activity. The CYP2A6 protein is most abundant in liver and is expressed, although at much lower levels, in some other tissues, especially nasal mucosa. CYP2A6 differs from other human liver CYP forms in that it participates in the metabolism of very few currently used drugs. The two most relevant substrates for CYP2A6 are coumarin and nicotine. Coumarin is the marker substance for determining CYP2A6 activity both in vitro and in vivo. Approximately 80% of a nicotine dose is eliminated by CYP2A6, and there is a clear link between CYP2A6 genotypes, smoking behavior, and lung cancer risk.