Research ArticlesMetabolism and Disposition of Resveratrol in the Isolated Perfused Rat Liver: Role of Mrp2 in the Biliary Excretion of Glucuronides
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INTRODUCTION
Resveratrol (trans‐3,5,4′‐trihydroxystilbene) is a polyphenolic phytoalexin found in grapes, fruits, and root extracts of Polygonum cuspidatum, an important constituent of Chinese folk medicine used to fight liver, skin, and circulatory diseases.1, 2 A great number of studies carried out in cellular and animal models have already demonstrated that resveratrol regulates many biological functions as it modulates lipid and lipoprotein metabolism,3, 4 inhibits platelet aggregation,5., 6., 7. alters
Materials
trans‐Resveratrol, sulfatase type V from Limpets (Patella vulgata), and β‐glucuronidase type B‐3 from bovine liver were obtained from Sigma (Munich, Germany). 14C‐Taurocholic acid was from NEN Life Science Products (Perkin‐Elmer, Wellesley, MA), bromosulfophthalein from Merck (Darmstadt, Germany). Methanol and water were of HPLC grade (Merck). All other chemicals and solvents were of analytical grade and used without further purification.
Liver Perfusion
The study was approved by the Animal Experimentation
Metabolism and Disposition of Resveratrol in Wistar Rats
Application of resveratrol (5–40 µM) to the liver of Wistar rats moderately stimulated bile flow between 6% and 30%. Choleresis reached its peak values at 10–15 min after addition of resveratrol to the perfusion medium (mean maximum values: 0.84 ± 0.09; 0.91 ± 0.11; 1.1 ± 0.07; 1.2 ± 0.13 µg/g liver/min, respectively), indicating moderate solvent drag by the concentrated excretion of resveratrol and its metabolites into bile. Afterwards, bile flow slowly declined reaching initial values after 90
DISCUSSION
In the present study, hepatic biotransformation and hepatobiliary transport of resveratrol and its metabolites was investigated by perfusing isolated rat livers of male Wistar rats with increasing concentrations of resveratrol (5–40 µM) which were chosen based on daily intakes of resveratrol as beverage (red wine) or as dietary supplement (5–25 mg/day). During 90 min the perfused liver extracted more than 99% of applied resveratrol with steady‐state concentrations attained within 5 min after
Acknowledgements
This study was supported by a grant from the Jubiläumsfonds der Österreichischen Nationalbank 9894 (W.J.) and by the Fonds zur Förderung der Wissenschaftlichen Forschung des Bürgermeisters der Bundeshauptstadt Wien (2296; T.S.).
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2018, Journal of Pharmaceutical SciencesCitation Excerpt :As is the case with resveratrol, these conjugate metabolites could be substrates for apical and basolateral membrane transporters. Resveratrol and its conjugate metabolites inhibited MRP2-mediated efflux of bromosulphothalein,56 and MRP3-mediated transport of estradiol-17-β-glucuronide.57 Influence of natural products on drug disposition is a developing science,8 and their effects on efflux transport are inherently complex.58
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2012, Archives of Biochemistry and BiophysicsCitation Excerpt :On the contrary, these proteins are also found in many other tissues (Fig. 6) thus affecting the distribution of some bioactive compounds present in the different organs [19]. Once trans-resveratrol arrives to the liver it undergoes a new process of phase II metabolism [60–61] and subsequent excretion of conjugates via the bile [49]. The remaining trans-resveratrol and derivatives in blood are distributed in different tissues and are eliminated by the kidney [12].
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