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?
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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口服“饮食可达”或“药理”剂量后[14C]-白藜芦醇在人前列腺组织中的分布和代谢：对抗癌活性有何影响？
DOI：
10.1093/ajcn/nqaa414
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发表时间：
2021-05-08
期刊：
影响因子：
--
通讯作者：
Brown K
中科院分区：
文献类型：
--
作者：
Cai H;Scott EN;Britton RG;Parrott E;Ognibene TJ;Malfatti M;Khan M;Steward WP;Brown K
膳食多酚白藜芦醇在临床前模型中预防各种恶性肿瘤，包括前列腺癌。尽管试图将研究结果转化为人类，但在理解药代动力学-药效学关系以及组织浓度如何影响疗效方面仍存在差距。这些信息对于剂量选择是必要的，并且考虑到白藜芦醇的低生物利用度，这些信息尤其重要。本研究的目的是确定男性前列腺组织中白藜芦醇的浓度后，饮食（5毫克）或药理学（1克）剂量。然后，我们研究了临床相关浓度的白藜芦醇/其代谢产物是否在前列腺细胞系中具有直接的抗癌活性。进行了一项窗口试验，在前列腺活检前，患者被分配到每天5 mg或1 g白藜芦醇，或不进行干预。患者（10/组）在活检前摄入白藜芦醇胶囊7-14天，最后一次剂量[14 C]标记，允许使用加速器MS检测前列腺组织中的白藜芦醇种类。分别使用HPLC和UV检测和细胞计数在癌症和非恶性细胞培养物中评估白藜芦醇/代谢物的细胞摄取和抗增殖特性。[14 C]-白藜芦醇种类在所有分析患者的前列腺组织中均可检测到，平均值± SD浓度为0.08 ± 0.04，而5 mg和1 g剂量分别为22.1 ± 8.2 pmol/mg组织。然而，总[14 C]-白藜芦醇当量在前列腺低于我们以前报道的血浆和结肠直肠相同剂量后。此外，白藜芦醇在前列腺组织中检测不到;相反，硫酸盐和葡萄糖醛酸代谢物占主导地位。虽然白藜芦醇在体外7天内减少前列腺细胞数量，但所需浓度（≥10 µM）超过了血浆最大浓度。白藜芦醇单硫酸盐和葡萄糖醛酸苷未能持续抑制细胞生长，部分原因是细胞吸收不良。白藜芦醇类物质的低组织浓度，加上其缀合物的弱抗增殖活性，表明≤1 g的每日剂量可能对人前列腺没有直接影响。该试验在clinicaltrialsregister.eu上注册为EudraCT 2007-002131-91。
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. 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. 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. [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. 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.
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DOI：
10.1016/j.bbadis.2015.01.014
发表时间：
2015-06-01
影响因子：
6.2
作者：
Park, Eun-Jung;Pezzuto, John M.
通讯作者：
Pezzuto, John M.
DOI：
10.1111/j.1749-6632.2010.05853.x
发表时间：
2011-01-01
期刊：
RESVERATROL AND HEALTH
影响因子：
--
作者：
Patel, Ketan R.;Scott, Edwina;Brown, Karen
通讯作者：
Brown, Karen
影响因子：
17.1
作者：
Cai H;Scott E;Kholghi A;Andreadi C;Rufini A;Karmokar A;Britton RG;Horner-Glister E;Greaves P;Jawad D;James M;Howells L;Ognibene T;Malfatti M;Goldring C;Kitteringham N;Walsh J;Viskaduraki M;West K;Miller A;Hemingway D;Steward WP;Gescher AJ;Brown K
通讯作者：
Brown K
DOI：
10.1016/j.jpba.2009.03.026
发表时间：
2010-01-20
影响因子：
3.4
作者：
Emilia Juan, M.;Maijo, Monica;Planas, Joana M.
通讯作者：
Planas, Joana M.
DOI：
10.1111/nyas.12205
发表时间：
2013-01-01
期刊：
RESVERATROL AND HEALTH
影响因子：
--
作者：
Gescher, Andreas;Steward, William P.;Brown, Karen
通讯作者：
Brown, Karen