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?

Autor: Masood A. Khan, Karen Brown, Michael A. Malfatti, Edwina N. Scott, William P. Steward, Emma Parrott, Robert G. Britton, Ted J. Ognibene, Hong Cai
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
Prostate biopsy
tissue distribution
Administration
Oral
Medicine (miscellaneous)
resveratrol
Pharmacology
Resveratrol
Antioxidants
AcademicSubjects/MED00160
AcademicSubjects/MED00060
03 medical and health sciences
chemistry.chemical_compound
Prostate cancer
0302 clinical medicine
Pharmacokinetics
Oral administration
Prostate
Cell Line
Tumor
accelerator mass spectrometry
Biopsy
Humans
Medicine
Carbon Radioisotopes
prostate
Nutrition and Dietetics
cancer prevention
Dose-Response Relationship
Drug
medicine.diagnostic_test
business.industry
Drug Administration Routes
Prostatic Neoplasms
medicine.disease
Diet
Bioavailability
Original Research Communications
030104 developmental biology
medicine.anatomical_structure
chemistry
Isotope Labeling
030220 oncology & carcinogenesis
window trial
business
metabolism
pharmacokinetics
Zdroj: The American Journal of Clinical Nutrition
ISSN: 0002-9165
DOI: 10.1093/ajcn/nqaa414
Popis: 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.
Databáze: OpenAIRE
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