In Vitro Glucuronidation and Sulfation of ε-Viniferin, a Resveratrol Dimer, in Humans and Rats

Courtois, Arnaud; Jourdes, Michaël; Dupin, Adeline; Lapèze, Caroline; Renouf, Elodie; Biais, Benoît; Teissèdre, Pierre-Louis; Mérillon, Jean‐Michel; Richard, Tristan; Krisa, Stéphanie

doi:10.3390/molecules22050733

Cited by 19 publications

(16 citation statements)

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“…The mass spectra obtained from plasma and tissue analysis showed the presence of ε-viniferin phase-II metabolites: glucuronide and sulphate conjugates. These metabolites, previously characterized in our laboratory, were identified as being V1G, V2G, V3G and V4G for glucuronides and V1S, V2S, V3S, and V4S for sulphates ( Figure 1 ) [ 16 ]. The plasma and tissue concentration-time profiles of total glucuronides and of total sulphates are shown in Figure 2 .…”

Section: Resultsmentioning

confidence: 99%

“…In a previous study using rat liver extracts, we showed that the in vitro metabolism of ε-viniferin produced four glucuronides (V1G, V2G, V3G and V4G) and four sulphates (V1S, V2S, V3S and V4S), with glucuronides being the major metabolites. V2G and V3G represented more than 90% of the total glucuronides, whereas sulphates metabolites were present in equal proportion [ 16 ]. We now confirm the same metabolic profile in vivo in rat liver both for glucuronides and sulphates, which is an important finding ( Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we described the in vitro metabolism of ε-viniferin using liver fractions. We found an intense metabolism in which more than 75% of the ε-viniferin was converted into glucuronide and sulphate metabolites in rat and human [ 16 ]. Mao and co-workers described the pharmacokinetic profile of δ-viniferin, another dehydrodimer of trans -resveratrol, in rats [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Tissular Distribution and Metabolism of trans-ε-Viniferin after Intraperitoneal Injection in Rat

et al. 2018

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Background: Recent studies showed that trans-ε-viniferin (ε-viniferin), a trans-resveratrol dehydrodimer, has anti-inflammatory and anti-obesity effects in rodents. The main purpose of this work was to assess the tissue distribution study of ε-viniferin and its metabolites after intraperitoneal (IP) administration in rat. Methods: After IP injection of 50 mg/kg, ε-viniferin and its metabolites were identified and quantified in plasma, liver, kidneys, adipose tissues, urine, and faeces by Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS). Results: ε-Viniferin underwent a rapid hepatic metabolism mostly to glucuronides but also to a lesser extent to sulphate derivatives. The highest glucuronide concentrations were found in liver followed by plasma and kidneys whereas only traces amounts were found in adipose tissues. In contrast the highest ε-viniferin areas under concentration (AUC) and mean residence times (MRT) values were found in white adipose tissues. Finally, much lower levels of ε-viniferin or its metabolites were found in urine than in faeces, suggesting that biliary excretion is the main elimination pathway. Conclusion: A rapid and large metabolism of ε-viniferin and a high bioaccumulation in white adipose tissues were observed. Thus, these tissues could be a reservoir of the native form of ε-viniferin that could allow its slow release and a sustained presence within the organism.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tissular Distribution and Metabolism of trans-ε-Viniferin after Intraperitoneal Injection in Rat

et al. 2018

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“…After oral consumption, resveratrol is primarily metabolized by phase II enzymes, especially glucuronides and sulfatases, and absorbed in the small gut, predominantly in its glucuronidated form [ 12 , 56 ]. In addition to the glucuronide metabolite, sulfated products of resveratrol are also commonly found in biological samples [ 57 ]; however, only trace amounts of free resveratrol can be detected in plasma [ 58 ]. In this regard, Sergides et al [ 59 ] demonstrated higher plasma concentrations of glucuronidated (4083.9 ± 1704.4 ng/ml) and sulfated (1516.0 ± 639.0 ng/ml) resveratrol than its unmetabolized form (71.2 ± 42.4 ng/ml) following the consumption of a single resveratrol (500 mg) tablet in healthy volunteers.…”

Section: Resveratrol Plant Biosynthesis and Pharmacokineticsmentioning

confidence: 99%

Neuroprotective Mechanisms of Resveratrol in Alzheimer’s Disease: Role of SIRT1

Gomes

Silva

Romeiro

et al. 2018

Oxidative Medicine and Cellular Longevity

273

201

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Alzheimer's disease (AD) is a progressive and neurodegenerative disorder of the cortex and hippocampus, which eventually leads to cognitive impairment. Although the etiology of AD remains unclear, the presence of β-amyloid (Aβ) peptides in these learning and memory regions is a hallmark of AD. Therefore, the inhibition of Aβ peptide aggregation has been considered the primary therapeutic strategy for AD treatment. Many studies have shown that resveratrol has antioxidant, anti-inflammatory, and neuroprotective properties and can decrease the toxicity and aggregation of Aβ peptides in the hippocampus of AD patients, promote neurogenesis, and prevent hippocampal damage. In addition, the antioxidant activity of resveratrol plays an important role in neuronal differentiation through the activation of silent information regulator-1 (SIRT1). SIRT1 plays a vital role in the growth and differentiation of neurons and prevents the apoptotic death of these neurons by deacetylating and repressing p53 activity; however, the exact mechanisms remain unclear. Resveratrol also has anti-inflammatory effects as it suppresses M1 microglia activation, which is involved in the initiation of neurodegeneration, and promotes Th2 responses by increasing anti-inflammatory cytokines and SIRT1 expression. This review will focus on the antioxidant and anti-inflammatory neuroprotective effects of resveratrol, specifically on its role in SIRT1 and the association with AD pathophysiology.

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“…For example, viniferin exhibited hepatoprotective activity and had a potent inhibitory effect against lipoxygenase and the oxidation of low-density lipoprotein and high-density lipoprotein [35]. It was also shown to prevent inflammation [36]. Furthermore, vinifirin was even identified as an anti-Alzheimer’s agent.…”

Section: Discussionmentioning

confidence: 99%

Plant-Derived Purification, Chemical Synthesis, and In Vitro/In Vivo Evaluation of a Resveratrol Dimer, Viniferin, as an HCV Replication Inhibitor

Lee

Mailar

Kim

et al. 2019

Viruses

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Oligostilbenoid compounds, a group of resveratrol multimers, display several anti-microbial activities through the neutralization of cytotoxic oxidants, and by inhibiting essential host and viral enzymes. In our previous study, we identified a series of oligostilbenoid compounds as potent hepatitis C virus (HCV) replication inhibitors. In particular, vitisin B, a resveratrol tetramer, exhibited the most dramatic anti-HCV activity (EC50 = 6 nM and CC50 > 10 μM) via the disruption of the viral helicase NS3 (IC50 = 3 nM). However, its further development as an HCV drug candidate was halted due to its intrinsic drawbacks, such as poor stability, low water solubility, and restricted in vivo absorption. In order to overcome these limitations, we focused on (+)-ε-viniferin, a resveratrol dimer, as an alternative. We prepared three different versions of (+)-ε-viniferin, including one which was extracted from the grapevine root (EVF) and two which were chemically synthesized with either penta-acetylation (SVF-5Ac) or no acetylation (SVF) using a newly established synthesis method. We confirmed their anti-HCV replication activities and minimal cytotoxicity by using genotype 1b and 2a HCV replicon cells. Their anti-HCV replication action also translated into a significant reduction of viral protein expression. Anti-HCV NS3 helicase activity by EVF was also verified in vitro. Finally, we demonstrated that SVF has improved pharmacokinetic properties over vitisin B. Overall, the favorable antiviral and pharmacokinetic properties of these three versions of viniferin warrant their further study as members of a promising new class of anti-HCV therapeutics.

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In Vitro Glucuronidation and Sulfation of ε-Viniferin, a Resveratrol Dimer, in Humans and Rats

Cited by 19 publications

References 40 publications

Tissular Distribution and Metabolism of trans-ε-Viniferin after Intraperitoneal Injection in Rat

Tissular Distribution and Metabolism of trans-ε-Viniferin after Intraperitoneal Injection in Rat

Neuroprotective Mechanisms of Resveratrol in Alzheimer’s Disease: Role of SIRT1

Plant-Derived Purification, Chemical Synthesis, and In Vitro/In Vivo Evaluation of a Resveratrol Dimer, Viniferin, as an HCV Replication Inhibitor

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