Safety assessment of Urolithin A, a metabolite produced by the human gut microbiota upon dietary intake of plant derived ellagitannins and ellagic acid. (October 2017)

• Record Type: Journal Article
• Authors: Heilman, Jacqueline; Andreux, Pénélope; Tran, Nga; Rinsch, Chris; Blanco-Bose, William
• Is Part Of: Food and chemical toxicology. Volume 108(2017)Part A
• Page Start: 289
• Page End: 297
• Publication Date: 2017-10
• Subjects: Urolithin -- Ellagitannin -- Ellagic acid -- Pomegranate; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2017.07.050
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Urolithins are metabolites produced in the gut following consumption of ellagitannins and ellagic acid rich foods such as pomegranates, nuts and certain berries. Urolithin A (UA) is one of the predominant isoforms of urolithins in humans and has demonstrated compelling biological activities, suggesting potential benefits of direct consumption of UA. However, an evaluation of the safety of direct administration of UA has not yet been published. The aim of this study was to investigate for the first time the genotoxicity, toxicokinetics, and repeated dose safety of orally administered synthetic UA in rats. The battery of genotoxicity assays demonstrated that UA is not genotoxic. The ADME study showed that glucuronidated and sulfonated forms of UA are the predominant metabolites following both oral and i.v. administration. The 28-day (0, 0.175, 1.75, and 5.0% UA mixed in diet) and 90-day studies (0, 1.25, 2.5, and 5.0% UA mixed in diet) showed no alterations in clinical parameters, blood chemistry, or hematology, and did not indicate any target organs, or any specific toxic mechanisms. The NOAEL was the highest dose tested, 5% UA by weight in the diet, or 3451 mg/kg bw/day in males and 3826 mg/kg bw/day in females in the 90-day oral study. Highlights: This study reports for the first time the safety profile of directly administered Urolithin A. The battery of genotoxicity assays demonstrated that Urolithin A is not genotoxic. The ADME study showed that glucuronidated and sulfonated forms of Urolithin A are the predominant metabolites. There were no adverse effects observed in the 28- and 90-day oral studies. The NOAEL was the highest dose tested in the 90-day oral study: 3451 and 3826 mg/kg/day in males and females respectively.