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Distribution and metabolism of [14C]-resveratrol in human prostate tissue after oral administration of a “dietary-achievable” or “pharmacological” dose: what are the implications for anticancer activity?

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posted on 10.05.2021, 13:49 by Hong Cai, Edwina N Scott, Robert G Britton, Emma Parrott, Ted J Ognibene, Michael Malfatti, Masood Khan, William P Steward, Karen Brown

Background

The dietary polyphenol resveratrol prevents various malignancies in preclinical models, including prostate cancer. Despite attempts to translate findings to humans, gaps remain in understanding pharmacokinetic-pharmacodynamic relations and how tissue concentrations affect efficacy. Such information is necessary for dose selection and is particularly important given the low bioavailability of resveratrol.

Objectives

This study aimed to determine concentrations of resveratrol in prostate tissue of men after a dietary-achievable (5 mg) or pharmacological (1 g) dose. We then examined whether clinically relevant concentrations of resveratrol/its metabolites had direct anticancer activity in prostate cell lines.

Methods

A window trial was performed in which patients were allocated to 5 mg or 1 g resveratrol daily, or no intervention, before prostate biopsy. Patients (10/group) ingested resveratrol capsules for 7-14 d before biopsy, with the last dose [14C]-labeled, allowing detection of resveratrol species in prostate tissue using accelerator MS. Cellular uptake and antiproliferative properties of resveratrol/metabolites were assessed in cancer and nonmalignant cell cultures using HPLC with UV detection and cell counting, respectively.

Results

[14C]-Resveratrol species were detectable in prostate tissue of all patients analyzed, with mean ± SD concentrations of 0.08 ± 0.04 compared with 22.1 ± 8.2 pmol/mg tissue for the 5 mg and the 1 g dose, respectively. However, total [14C]-resveratrol equivalents in prostate were lower than we previously reported in plasma and colorectum after identical doses. Furthermore, resveratrol was undetectable in prostate tissue; instead, sulfate and glucuronide metabolites dominated. Although resveratrol reduced prostate cell numbers in vitro over 7 d, the concentrations required (≥10 µM) exceeded the plasma maximum concentration. Resveratrol mono-sulfates and glucuronides failed to consistently inhibit cell growth, partly due to poor cellular uptake.

Conclusions

Low tissue concentrations of resveratrol species, coupled with weak antiproliferative activity of its conjugates, suggest daily doses of ≤1 g may not have direct effects on human prostate.This trial was registered at clinicaltrialsregister.eu as EudraCT 2007-002131-91.

History

Citation

The American Journal of Clinical Nutrition, Volume 113, Issue 5, May 2021, Pages 1115–1125, https://doi.org/10.1093/ajcn/nqaa414

Author affiliation

Leicester Cancer Research Centre, University of Leicester

Version

VoR (Version of Record)

Published in

The American journal of Clinical Nutrition

Volume

113

Issue

5

Pagination

1115-1125

Publisher

Oxford University Press (OUP)

issn

0002-9165

eissn

1938-3207

Acceptance date

08/12/2020

Copyright date

2021

Available date

10/05/2021

Spatial coverage

United States

Language

eng