Investigation of the absorption of resveratrol oligomers in the Caco-2 cellular model of intestinal absorption

Willenberg, Ina; Michael, Maria; Wonik, Jasmin; Bartel, Laura C.; Empl, Michael T.; Schebb, Nils Helge

doi:10.1016/j.foodchem.2014.06.103

Cited by 69 publications

(45 citation statements)

References 36 publications

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“…24, 25 Cell monolayers that exceeded a resistance of 300 Ω cm −2 were incubated with either 1 μM or 10 μM of TPPU solution in DMSO on the apical side. Medium samples on the apical and basolateral side were collected and frozen immediately after 1, 3 and 6 hours.…”

Section: Methodsmentioning

confidence: 99%

Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern

Ostermann¹,

Herbers²,

Willenberg³

et al. 2015

Prostaglandins & Other Lipid Mediators

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Epoxides from polyunsaturated fatty acids (PUFAs) are potent lipid mediators. In vivo stabilization of these epoxides by blockade of the soluble epoxide hydrolase (sEH) leads to anti-inflammatory, analgesic and normotensive effects. Therefore, sEH inhibitors (sEHi) are a promising new class of drugs. Herein, we characterized pharmacokinetic (PK) and pharmacodynamic properties of a commercially available potent sEHi 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU). Cell culture studies suggest its high absorption and metabolic stability. Following administration in drinking water to rats (0.2, 1, and 5 mg TPPU/L with 0.2% PEG400), TPPU’s blood concentration increased dose dependently within the treatment period to reach an almost steady state after 8 days. TPPU was found in all the tissues tested. The linoleic epoxide/diol ratios in the tissues were dose dependently increased, indicating significant sEH inhibition. Overall, administration of TPPU with the drinking water led to systemic distribution as well as high levels and thusmakes chronic sEH inhibition studies possible.

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Section: Methodsmentioning

confidence: 99%

Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern

Ostermann¹,

Herbers²,

Willenberg³

et al. 2015

Prostaglandins & Other Lipid Mediators

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“…Furthermore, resveratrol oligomers, ε‐viniferin (dimer), and hopeaphenol (tetramer), exhibited very low apparent permeability values (0.3 × 10 −6 cm/s for ε‐viniferin and 1.4 × 10 −6 cm/s for hopeaphenol) in the Caco‐2 transwell system. Thus, oral absorption of ε‐viniferin and hopeaphenol is low compared to that of resveratrol .…”

Section: Resultsmentioning

confidence: 99%

Development and validation of a liquid chromatography with tandem mass spectrometry method for the quantification of vitisin B in rat plasma and urine

et al. 2015

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A new, rapid, and sensitive liquid chromatography with tandem mass spectrometry method was developed for the determination of vitisin B and validated in rat plasma and urine using carbamazepine as an internal standard. The plasma (0.05 mL) or urine (0.2 mL) samples were extracted by liquid-liquid extraction with ethyl acetate and separated on an Eclipse Plus C18 column (100 × 4.6 mm, 3.5 μm) with a mobile phase consisting of acetonitrile and 0.1% formic acid water (60:40, v/v) at a flow rate of 0.7 mL/min. Detection and quantification were performed by mass spectrometry in selected reaction-monitoring mode with positive electrospray ionization. The calibration curves were recovered over the concentration ranges of 10-5000 ng/mL (correlation coefficients, r≥0.9833) in plasma and 5-2500 ng/mL (r≥0.9977) in urine, respectively. All validation data, including the specificity, precision, accuracy, recovery, and stability, conformed to the acceptance requirements. No matrix effects were observed. The developed method was successfully applied to pharmacokinetic studies of vitisin B following intravenous administration of 0.5 and 1 mg/kg and intraperitoneal injection of 5, 10, and 25 mg/kg to rats. This is the first report on the pharmacokinetic properties of vitisin B. The results provide a meaningful basis to evaluate preclinical or clinical applications of vitisin B.

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“…resveratrol; reviewed in [14]) are prone to fast metabolization [64], or are, although not metabolized, not taken up by cells at all (e.g. the resveratrol oligomer hopeaphenol) [22]. Therefore, an analysis of the metabolism/metabolic stability of a compound should always be an integral part of the overall assessment of its biological or anticarcinogenic activity.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, it is not surprising that a number of studies proposing the search for molecules more suited for use in cancer therapy or chemoprevention and/or investigating the anticarcinogenic/chemopreventive efficacy as well as metabolic stability of natural or synthetic compounds related to resveratrol have been published (e.g. [15–22]).…”

Section: Introductionmentioning

confidence: 99%

Growth-Inhibiting Activity of Resveratrol Imine Analogs on Tumor Cells In Vitro

Wang¹,

Willenberg²,

Krohn

et al. 2017

PLoS ONE

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Although resveratrol exerts manifold antitumorigenic effects in vitro, its efficacy against malignancies in vivo seems limited. This has been increasingly recognized in recent years and has prompted scientists to search for structurally related compounds with more promising anticarcinogenic and/or pharmacokinetic properties. A class of structurally modified resveratrol derivatives, so-called resveratrol imine analogs (IRA’s), might meet these requirements. Therefore, the biological activity of five of these compounds was examined and compared to that of resveratrol. Firstly, the antiproliferative potency of all five IRA’s was investigated using the p53 wildtype-carrying colorectal carcinoma cell line HCT-116wt. Then, using the former and a panel of various other tumor cell lines (including the p53 knockout variant HCT-116p53-/-), the growth-inhibiting and cell cycle-disturbing effects of the most potent IRA (IRA 5, 2-[[(2-hydroxyphenyl)methylene]amino]-phenol) were studied as was its influence on cyclooxygenase-2 expression and activity. Finally, rat liver microsomes were used to determine the metabolic stability of that compound. IRA 5 was clearly the most potent compound in HCT-116wt cells, with an unusually high IC50-value of 0.6 μM. However, in the other five cell lines used, the antiproliferative activity was mostly similar to resveratrol and the effects on the cell cycle were heterogeneous. Although all cell lines were affected by treatment with IRA 5, cells expressing functional p53 seemed to react more sensitively, suggesting that this protein plays a modulating role in the induction of IRA 5-mediated biological effects. Lastly, IRA 5 led to contradictory effects on cyclooxygenase-2 expression and activity and was less glucuronidated than resveratrol. As IRA 5 is approximately 50 times more toxic towards HCT-116wt cells, exerts different effects on the cyclooxygenase-2 and is metabolized to a lesser extent, it shows certain advantages over resveratrol and could therefore serve as basis for additional chemical modifications, potentially yielding compounds with more favorable biological and pharmacokinetic features.

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Investigation of the absorption of resveratrol oligomers in the Caco-2 cellular model of intestinal absorption

Cited by 69 publications

References 36 publications

Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern

Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern

Development and validation of a liquid chromatography with tandem mass spectrometry method for the quantification of vitisin B in rat plasma and urine

Growth-Inhibiting Activity of Resveratrol Imine Analogs on Tumor Cells In Vitro

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