Sulforaphane Bioavailability and Chemopreventive Activity in Men Presenting for Biopsy of the Prostate Gland: A Randomized Controlled Trial

Zhang, Zhenzhen; Garzotto, Mark; Davis, Edward W.; Mori, Motomi; Stoller, Wesley; Farris, Paige E.; Wong, Carmen P.; Beaver, Laura M.; Thomas, George V.; Williams, David E.; Dashwood, Roderick H.; Hendrix, David A.; Ho, Emily; Shannon, Jackilen

doi:10.1080/01635581.2019.1619783

Cited by 49 publications

(59 citation statements)

References 46 publications

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“…In a double-blind randomized placebo-controlled trial in men presenting for prostate biopsy, plasma levels of 0.12 µM of sulforaphane and its metabolites were detected after an intervention period of 4–8 weeks with two daily doses of 100 μmol sulforaphane administered 12 h apart [58]. Isothiocyanate levels of 2.2 µM and 500 nM were detected in the plasma and synovial fluid, respectively of patients with osteoarthritis undergoing knee replacement surgery following consumption of glucosinolate-rich diets for 2 weeks [59].…”

Section: Broccoli-based Clinical Trialsmentioning

confidence: 99%

Broccoli or Sulforaphane: Is It the Source or Dose That Matters?

et al. 2019

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There is robust epidemiological evidence for the beneficial effects of broccoli consumption on health, many of them clearly mediated by the isothiocyanate sulforaphane. Present in the plant as its precursor, glucoraphanin, sulforaphane is formed through the actions of myrosinase, a β-thioglucosidase present in either the plant tissue or the mammalian microbiome. Since first isolated from broccoli and demonstrated to have cancer chemoprotective properties in rats in the early 1990s, over 3000 publications have described its efficacy in rodent disease models, underlying mechanisms of action or, to date, over 50 clinical trials examining pharmacokinetics, pharmacodynamics and disease mitigation. This review evaluates the current state of knowledge regarding the relationships between formulation (e.g., plants, sprouts, beverages, supplements), bioavailability and efficacy, and the doses of glucoraphanin and/or sulforaphane that have been used in pre-clinical and clinical studies. We pay special attention to the challenges for better integration of animal model and clinical studies, particularly with regard to selection of dose and route of administration. More effort is required to elucidate underlying mechanisms of action and to develop and validate biomarkers of pharmacodynamic action in humans. A sobering lesson is that changes in approach will be required to implement a public health paradigm for dispensing benefit across all spectrums of the global population.

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Section: Broccoli-based Clinical Trialsmentioning

confidence: 99%

Broccoli or Sulforaphane: Is It the Source or Dose That Matters?

et al. 2019

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“…Another study reported plasma dithiocarbamate levels of 0.92 ± 0.72 μM and mean epithelial-/stromal-enriched breast tissue dithiocarbamate concentration of 1.45 ± 1.12 and 2.00 ± 1.95 pmol/mg tissue for the right and the left breast, respectively, in eight healthy women undergoing reduction mammoplasty who had received a single dose of a broccoli sprout preparation delivering 200 μmol sulforaphane 1 h prior to surgery ( 47 ). In a double-blind randomized placebo-controlled trial in men presenting for prostate biopsy, plasma levels of 0.12 μM of sulforaphane, and its metabolites were detected after an intervention period of 4–8 weeks with two daily doses of 100 μmol sulforaphane administered 12 h apart ( 65 ). Collectively, these studies rather consistently indicate that sulforaphane reaches only low micromolar peak plasma concentrations and exhibits a short biological half-life in clinical trial settings.…”

Section: Study Cohorts: Pharmacokinetics Biomarkers Of Pharmacodynamic Action and Other Outcomes In Clinical Trialsmentioning

confidence: 99%

The Challenges of Designing and Implementing Clinical Trials With Broccoli Sprouts… and Turning Evidence Into Public Health Action

Fahey

Kensler

2021

Front. Nutr.

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Broccoli sprouts are a convenient and rich source of the glucosinolate glucoraphanin, which can generate the chemopreventive agent sulforaphane through the catalytic actions of plant myrosinase or β-thioglucosidases in the gut microflora. Sulforaphane, in turn, is an inducer of cytoprotective enzymes through activation of Nrf2 signaling, and a potent inhibitor of carcinogenesis in multiple murine models. Sulforaphane is also protective in models of diabetes, neurodegenerative disease, and other inflammatory processes, likely reflecting additional actions of Nrf2 and interactions with other signaling pathways. Translating this efficacy into the design and implementation of clinical chemoprevention trials, especially food-based trials, faces numerous challenges including the selection of the source, placebo, and dose as well as standardization of the formulation of the intervention material. Unlike in animals, purified sulforaphane has had very limited use in clinical studies. We have conducted a series of clinical studies and randomized clinical trials to evaluate the effects of composition (glucoraphanin-rich [± myrosinase] vs. sulforaphane-rich or mixture beverages), formulation (beverage vs. tablet) and dose, on the efficacy of these broccoli sprout-based preparations to evaluate safety, pharmacokinetics, pharmacodynamic action, and clinical benefit. While the challenges for the evaluation of broccoli sprouts in clinical trials are themselves formidable, further hurdles must be overcome to bring this science to public health action.

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“…They have been identified principally in cell culture screens. Several comprehensive reviews of this topic have been published recently [ 193 , 199 ]. These molecules can be natural products, natural product-derived, or natural product-inspired.…”

Section: Pharmacological Inducers Of Keap1-nrf2 Signalingmentioning

confidence: 99%

“…Comprehensive, unbiased analyses for gene expression (e.g., microarray, RNA-sequencing, and ChIP-seq) have provided powerful assessments for gene expression profiling and transcriptional networks. Several studies, principally focused on SFN, have been performed [ 128 , 131 , 193 ], revealing characteristic and novel gene expression profiling correlated with intervention.…”

Section: Biomarker-based Clinical Studies and Nrf2 Inducersmentioning

confidence: 99%

Current Landscape of NRF2 Biomarkers in Clinical Trials

et al. 2020

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The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) plays a critical role in the maintenance of cellular redox and metabolic homeostasis, as well as the regulation of inflammation and cellular detoxication pathways. The contribution of the NRF2 pathway to organismal homeostasis is seen in many studies using cell lines and animal models, raising intense attention towards targeting its clinical promise. Over the last three decades, an expanding number of clinical studies have examined NRF2 inducers targeting an ever-widening range of diseases. Full understanding of the pharmacokinetic and pharmacodynamic properties of drug candidates rely partly on the identification, validation, and use of biomarkers to optimize clinical applications. This review focuses on results from clinical trials with four agents known to target NRF2 signaling in preclinical studies (dimethyl fumarate, bardoxolone methyl, oltipraz, and sulforaphane), and evaluates the successes and limitations of biomarkers focused on expression of NRF2 target genes and others, inflammation and oxidative stress biomarkers, carcinogen metabolism and adduct biomarkers in unavoidably exposed populations, and targeted and untargeted metabolomics. While no biomarkers excel at defining pharmacodynamic actions in this setting, it is clear that these four lead clinical compounds do touch the NRF2 pathway in humans.

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Sulforaphane Bioavailability and Chemopreventive Activity in Men Presenting for Biopsy of the Prostate Gland: A Randomized Controlled Trial

Cited by 49 publications

References 46 publications

Broccoli or Sulforaphane: Is It the Source or Dose That Matters?

Broccoli or Sulforaphane: Is It the Source or Dose That Matters?

The Challenges of Designing and Implementing Clinical Trials With Broccoli Sprouts… and Turning Evidence Into Public Health Action

Current Landscape of NRF2 Biomarkers in Clinical Trials

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