Subchronic oral toxicity and cardiovascular safety pharmacology studies of resveratrol, a naturally occurring polyphenol with cancer preventive activity

Life Sciences Group, IIT Research Institute, Chicago, Illinois 60616, USA.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association (Impact Factor: 2.9). 09/2011; 49(12):3319-27. DOI: 10.1016/j.fct.2011.08.023
Source: PubMed


To characterize the subchronic oral toxicity of resveratrol, CD rats received daily gavage doses of 0, 200, 400, or 1000 mg resveratrol/kg/day, and beagle dogs received daily capsule doses of 0, 200, 600, or 1200 mg resveratrol/kg/day for 90 days. Resveratrol induced only minimal toxicity, consisting of dose-related reductions in body weight gain in female rats and both sexes of dogs, and a statistically significant increase in bilirubin levels in rats at the 1000 mg/kg/day dose. Clinical observations, hematology, ophthalmology, neurotoxicity evaluations (functional observational batteries), organ weights, and gross pathology provided no biologically significant evidence of resveratrol toxicity in either species. In rats, the high dose of resveratrol reduced the incidence of cardiomyopathy; no other microscopic changes were seen. Histopathologic changes in dogs were limited to minimal inflammatory infiltrates in the kidney and urinary bladder, which were not considered toxicologically significant. A cardiovascular safety pharmacology (telemetry) study in dogs revealed no evidence of resveratrol toxicity. Based on body weight effects, the No Observed Adverse Effect Level (NOAEL) for resveratrol was 200mg/kg/day in rats and 600 mg/kg/day in dogs. The apparent cardioprotective activity of resveratrol in rats demonstrates that its potentially beneficial activities may extend beyond efficacy in cancer prevention.

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    • "The resveratrol (RSV, 3,4´,5-trihydroxystilbene) is a phytoalexin that is naturally found in several plants, including grape, red wine, berries and peanuts [4] and can effectively scavenge intracellular free radicals and different oxidants in various cell types [5] [6]. Jang et al. [7] demonstrating for the first time anticarcinogenic effects of RSV then this compound have been studied in cancer researchers since 1997. "
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    ABSTRACT: The resveratrol (RSV, 3,4',5-trihydroxy stilbene) is a phytoalexin which is naturally occurring in different plants. The in vivo antigenotoxic effects of RSV against ethyl methane sulfonate (EMS) and potassium dichromate (K2Cr2O7) which causes genotoxicity with different mechanisms was studied in Drosophila melanogaster by using the Drosophila SMART assay and the alkaline Comet assay. For SMART assay the larvae were treated both pre-treatments and co-treatments, for Comet assay the larvae were treated simultaneous exposure. The results from the SMART assay showed that in pre-treatments and co-treatments of RSV with EMS and K2Cr2O7 was reduced the genotoxicity in all concentrations excluding only 1 mM concentration in co-treatments of RSV with EMS. Antigenotoxic effects of RSV against EMS and K2Cr2O7 is higher in pretreatment compared to co-treatment and stronger in especially against genotoxic damage caused by K2Cr2O7. In results of Comet assay RSV showed antigenotoxic effects against genotoxic damage caused by EMS and K2Cr2O7 for tail intensity (%) and tail moment (mu m). These results confirm the usefulness of the Comet assay with haemocytes as an in vivo model and support the possibility of antigenotoxicity associated with RSV. This is the first study reporting antigenotoxicity data in somatic cells of Drosophila for RSV.
    Fresenius Environmental Bulletin 05/2014; 23(9). · 0.38 Impact Factor
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    • "The prevalence of these two metabolites has been found in several species, such as mouse [11] and pig [14], [30]. This result is less clear in rat [33], [42] and dog [13], [43] (see Table 3). However, when high doses of the pure resveratrol trans-isoform are administered, resveratrol sulfate derivatives have been found to be the main metabolites in humans [32], [38], [39], [44], [45], [46], [47]. "
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    ABSTRACT: The grey mouse lemur (Microcebus murinus) is a non-human primate used to study the ageing process. Resveratrol is a polyphenol that may increase lifespan by delaying age-associated pathologies. However, no information about resveratrol absorption and metabolism is available for this primate. Resveratrol and its metabolites were qualitatively and quantitatively analyzed in male mouse-lemur plasma (after 200 of oral resveratrol) by ultra-high performance liquid chromatography (UHPLC), coupled to a quadrupole-time-of-flight (Q-TOF) mass spectrometer used in full-scan mode. Data analyses showed, in MSE mode, an ion common to resveratrol and all its metabolites: m/z 227.072, and an ion common to dihydro-resveratrol metabolites: m/z 229.08. A semi-targeted study enabled us to identify six hydrophilic resveratrol metabolites (one diglucurono-conjugated, two monoglucurono-conjugated, one monosulfo-conjugated and two both sulfo- and glucurono-conjugated derivatives) and three hydrophilic metabolites of dihydro-resveratrol (one monoglucurono-conjugated, one monosulfo-conjugated, and one both sulfo- and glucurono-conjugated derivatives). The presence of such metabolites has been already detected in the mouse, rat, pig, and humans. Free resveratrol was measurable for several hours in mouse-lemur plasma, and its two main metabolites were trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate. Free dihydro-resveratrol was not measurable whatever the time of plasma collection, while its hydrophilic metabolites were present at 24 h after intake. These data will help us interpret the effect of resveratrol in mouse lemurs and provide further information on the inter-species characteristics of resveratrol metabolism.
    PLoS ONE 03/2014; 9(3):e91932. DOI:10.1371/journal.pone.0091932 · 3.23 Impact Factor
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    • "Resveratrol improved memory deficits in mice fed a high-fat diet [551]. Subchronic oral toxicity and cardiovascular safety pharmacology studies were carried out [552]. The biosynthesis of resveratrol in yeast and in mammalian cells was achieved [553]. "
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