Endothelial Cells Deconjugate Resveratrol Metabolites to Free Resveratrol: A Possible Role in Tissue Factor Modulation

Abstract

Scope The antithrombotic effects of resveratrol (RV) and its derivatives remain unknown. The objective is to evaluate the modulatory effects of RV, its glucoside form, piceid, and its biological metabolites (RV‐3‐O‐β‐d‐glucuronide, RV‐4’‐O‐d‐glucuronide, and RV‐3‐O‐sulfate) on tissue factor (TF). Moreover, the endothelial metabolism of RV is assessed. Methods and results Human aortic endothelial cells (HAECs) are incubated with trans‐piceid, trans‐RV, or their biological metabolites and stimulated with tumor necrosis factor‐α (TNF‐α). TF activity, protein levels, and mRNA expression are determined in cell lysates. Moreover, RV conjugation (phase‐II‐metabolism) to its sulfated or glucuronidated metabolites and their deconjugation to their parent compound (free RV) are also assessed in cell lysates and culture media. RV decreased TF activity, protein levels, and mRNA expression, whereas piceid and RV metabolites (RVmet) had no effects. RV‐3‐O‐sulfate was the main metabolite generated in the endothelium, while RVmet are deconjugated to free RV. Isomerization of trans‐RV and its trans‐metabolites to their cis‐forms is observed. Conclusions RV exerts antithrombotic effects by modulating TF. RVmet and piceid does not exert this effect. However, the capacity of endothelial cells to deconjugate RVmet to free RV indicates that RVmet function as an endothelial reservoir for RV regeneration, thus, contributing to the antithrombotic effects of RV.

Resveratrol Treatment Enhances the Cellular Response to Leptin by Increasing OBRb Content in Palmitate-Induced Steatotic HepG2 Cells

“…In addition, RSV was stable in the absence of cells, which accounts for the lack of spontaneous degradation and the complete availability of RSV for the cells. This stability is also consistent with results obtained in human endothelial cells incubated with different forms of RSV [31].…”

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

“…Furthermore, sustained intake of 1 g of RSV as a food supplement resulted in a concentration of 50-640 μM RSV in human colonic tissues [27]. Moreover, sulfate metabolites of RSV contribute to the in vivo activity of these metabolites by regenerating free RSV in colorectal cell lines, supporting the hypothesis that RSV metabolites potentially serve as a reservoir for the parent compound [27,195]. These paradigm shifting studies have not only challenged the classical notion that low bioavailability of RSV is the reason for the lack of therapeutic effects in human clinical trials but have also provided a potential molecular basis for the unexpected effects of high-dose RSV in human clinical trials such as adverse gastrointestinal effects [196,197].…”

Generation of the Antioxidant Hydroxytyrosol from Tyrosol Present in Beer and Red Wine in a Randomized Clinical Trial

“…Previous authors have suggested that the low concentrations of the free forms observed in vivo cannot explain the biological activities associated with phenolic consumption in clinical and epidemiological studies [25]. Therefore, metabolites have been proposed as exhibiting relevant biological properties, either by having activity themselves or being deconjugated intracellularly giving rise to free active forms, as has been described for other dietary phenols [26,27]. In the present study we show an increase in TYR and HT phase II metabolite recovery following RW and beer treatments.…”