Sulfate Metabolites Provide an Intracellular Pool for Resveratrol Generation and Induce Autophagy with Senescence

Abstract

One Sentence Summary: Biologically active concentrations of resveratrol can be generated intracellularly following uptake of the major human sulfate metabolites by selected cells; at doses considered safe in humans, resveratrol produced via this route may be of greater importance than unmetabolised resveratrol for eliciting beneficial effects. Abstract:The phytochemical resveratrol is thought to exert numerous health benefits. Its rapid phase II metabolism and resulting poor bioavailability may limit translation of these effects to humans. It is conceivable, but unproven, that metabolites contribute to activity in vivo, perhaps via hydrolysis of conjugates regenerating the parent. We present the first accurate quantitation of resveratrol sulfate and glucuronide conjugates in human plasma and tissue following repeated ingestion of resveratrol. Pharmacokinetic characterisation of a mixture of resveratrol-3-and 4′-O-sulfates in mice demonstrates that these metabolites are orally absorbed, but have low bioavailability at ~14 and 3%, respectively. Sulfate hydrolysis in vivo, liberates free resveratrol, which accounts for ~2% of the total resveratrol species present in plasma. Monosulfate metabolites were also converted to the parent in human colorectal cells. The extent of cellular uptake was dependent on specific membrane transporters and dictated anti-proliferative activity. Sulfate metabolites induced autophagy and senescence in cancer cells.These effects were abrogated by inclusion of a sulfatase inhibitor, which reduced intracellular resveratrol, suggesting the parent compound elicits this activity. These findings demonstrate that resveratrol sulfates may contribute to efficacy in vivo, by delivering resveratrol to target tissues in a stable conjugated form enabling gradual regeneration of the parent within selected cells. At doses considered safe in humans resveratrol generated via this route may be of greater importance than unmetabolised resveratrol.

Anticancer Activities of Resveratrol in Colorectal Cancer

“…These findings support the use of resveratrol in the treatment of intestinal diseases and may contribute to the observed amelioration of CRC after resveratrol supplementation [6,7]. Resected colorectal tissue indeed contains traces of resveratrol and its metabolites, suggesting that, unlike cells located within internal organs, resveratrol metabolites can reach sufficiently high, anti-carcinogenic levels in responsive target cells within the gastrointestinal tract [6,24].…”

“…Patients diagnosed with CRC and fed resveratrol show statistically significant reductions in tumor proliferation [6,7]. This effect correlates with HPLC/UV/Mass Spectrometry-validated increases in resveratrol and its metabolites in resected colorectal tissues and suggests that, unlike cells located within internal organs, resveratrol metabolites can reach sufficiently high, anti-carcinogenic levels in responsive target cells within the gastrointestinal tract [6,24].…”

“…The desulfation of resveratrol was confirmed in mice: hydrolysis of the sulfate group yielded free resveratrol which accounted for 2% of the total resveratrol content in the plasma. The concentration of resveratrol-sulfate on the serosal side of the human intestine can reach approximately 640 μM, which is much higher than the concentration used in the in vitro experiments that showed a reduction in proliferation of 20% [24]. Through these findings, one may hypothesize that the observed beneficial effects of resveratrol in reducing CRC proliferation is mediated partially through resveratrol sulfate and partially through desulfation events, which yield the parent compound.…”

Determination of trans-resveratrol action on two different types of neuronal cells, neuroblastoma and hippocampal cells

“…Food Sci., 34, 2016 (2) data suggest that resveratrol is delivered to target tissues in a stable sulphate-conjugated form (Patel et al 2013). These metabolites are able to penetrate into the living cells where they are gradually regenerated into the parent compound.…”

Targeting extracellular matrix remodeling in disease: Could resveratrol be a potential candidate?

“…87 However, studies have also shown that monosulfates may be converted back to resveratrol intracellularly. 88 Hence, it is likely that after cellular delivery, monosulfates are recycled back to resveratrol, which then produces the biological effects. Development of appropriate formulations is another obstacle currently.…”