PT  - JOURNAL ARTICLE
AU  - Ryusuke Hosoda
AU  - Atsushi Kuno
AU  - Yusuke S Hori
AU  - Katsuki Ohtani
AU  - Nobutaka Wakamiya
AU  - Azusa Oohiro
AU  - Hiroki Hamada
AU  - Yoshiyuki Horio
TI  - Differential cell-protective function of two resveratrol (trans-3,5,4'-trihydroxystilbene) glucosides against oxidative stress
AID  - 10.1124/jpet.112.198937
DP  - 2012 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.112.198937
4099  - http://jpet.aspetjournals.org/content/early/2012/10/05/jpet.112.198937.short
4100  - http://jpet.aspetjournals.org/content/early/2012/10/05/jpet.112.198937.full
AB  - Resveratrol (trans-3,5,4'-trihydroxystilbene, RSV), a natural polyphenol, exerts a beneficial effect on health and diseases. RSV targets and activates the NAD+-dependent protein deacetylase SIRT1; in turn, SIRT1 induces an intracellular antioxidative mechanism by inducing mitochondrial superoxide dismutase (SOD2). Most RSV found in plants is glycosylated, and the effect of these glycosylated forms on SIRT1 has not been studied. Here, we compared the effects of RSV and two glycosyl RSVs, resveratrol-3-O-β-D-glucoside (3G-RSV) and resveratrol-4'-O-β-D-glucoside (4'G-RSV), at the cellular level. In oxygen radical absorbance capacity (ORAC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assays, 3G-RSV's antioxidant activity was comparable to that of RSV, while 4'G-RSV's radical-scavenging efficiency was less than 50% of that of RSV. However, 4'G-RSV, but not 3G-RSV, induced SIRT1-dependent histone H3 deacetylation and SOD2 expression in mouse C2C12 skeletal myoblasts; as with RSV, SIRT1 knockdown blunted these effects. RSV and 4'G-RSV, but not 3G-RSV, mitigated oxidative stress-induced cell death in C2C12 cells and primary neonatal rat cardiomyocytes. RSV and 4'G-RSV inhibited C2C12 cell proliferation, but 3G-RSV did not. RSV was found in both the intracellular and extracellular fractions of C2C12 cells that had been incubated with 4'G-RSV, indicating that 4'G-RSV was extracellularly deglycosylated to RSV, which was then taken up by the cells. C2C12 cells did not deglycosylate 3G-RSV. Our results point to 4'G-RSV as a useful RSV prodrug with high water solubility. These data also show that the in vitro antioxidative activity of these molecules did not correlated with their ability to protect cells from oxidative stress-induced apoptosis.