Oncogenicity evaluation of resveratrol in p53(±) (p53 knockout) mice

Abstract

A six-month study was conducted in p53 (+/-) mice to evaluate the possible oncogenicity of resveratrol (3,5,4'-trihydroxy-trans-stilbene), a cancer chemopreventive agent present in grapes and other foods. p53 (+/-) mice (25/sex/group) received daily gavage exposure to vehicle only (negative control), resveratrol doses of 1000, 2000, or 4000 mg/kg/day, or p-cresidine (400 mg/kg/day; positive control). No mortality was seen in mice receiving the low dose of resveratrol. However, the mid and high doses induced mortality associated with impaction of the test article in the gastrointestinal tract. Resveratrol had no effect on body weight, food consumption, or clinical signs in surviving mice in any dose group, but induced dose-related increases in liver weight and serum cholesterol in both sexes. Mild anemia was seen in male mice at the high dose only; hematologic effects were not seen in females. Histopathology identified the kidney (hydronephrosis) and urinary bladder (epithelial hyperplasia) as target tissues for resveratrol toxicity. The incidences of both benign and malignant tumors in mice exposed to resveratrol were comparable to those in vehicle controls. By contrast, the positive control article, p-cresidine, induced urinary bladder cancer in both sexes. When administered to p53 (+/-) mice at its maximum tolerated dose, resveratrol demonstrates no evidence of oncogenicity.

Sirtuin 1-mediated Effects of Exercise and Resveratrol on Mitochondrial Biogenesis

“…RSV was reconstituted in mouse chow at a concentration of 1 g/kg in a phytoestrogen-free control diet (29,30). This treatment was performed in conjunction with mice that were placed in cages with voluntary running wheels and trained over a 9-week period.…”

Enhancing the bioavailability of resveratrol by combining it with piperine

“…In mice, resveratrol has been shown to be well tolerated at doses as high as 5000 mg/kg/day, for 28 consecutive days; however, high doses were associated with mortality due to the impaction of resveratrol in the gastrointestinal tract [9]. In healthy human volunteers, resveratrol has been administered at doses as high as 5 g as a single dose or at 5 g daily for up to 28 days in two different studies [10, 11].…”

Safety of synthetic trans‐resveratrol as a novel food pursuant to Regulation (EC) No 258/97

“…In response to a Member State's comment to assess the risk of carcinogenicity, the applicant referred to a 6-month study with p53-knockout mice (Horn et al, 2007). In this study, synthetic trans-resveratrol with a purity of 99.5% produced by another manufacturer, was administered by gavage to groups of 10 male and 10 female animals per dose group (i.e.…”