Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial
Open accessAbstract
BACKGROUND: COPD patients have high pulmonary and systemic oxidative stress that correlates with severity of disease. Sulforaphane has been shown to induce expression of antioxidant genes via activation of a transcription factor, nuclear factor erythroid-2 related factor 2 (Nrf2). METHODS: This parallel, placebo-controlled, phase 2, randomized trial was conducted at three US academic medical centers. Patients who met GOLD criteria for COPD and were able to tolerate bronchoscopies were randomly assigned (1:1:1) to receive placebo, 25 μmoles, or 150 μmoles sulforaphane daily by mouth for four weeks. The primary outcomes were changes in Nrf2 target gene expression (NQ01, HO1, AKR1C1 and AKR1C3) in alveolar macrophages and bronchial epithelial cells. Secondary outcomes included measures of oxidative stress and airway inflammation, and pulmonary function tests. RESULTS: Between July 2011 and May 2013, 89 patients were enrolled and randomized. Sulforaphane was absorbed in the patients as evident from their plasma metabolite levels. Changes in Nrf2 target gene expression relative to baseline ranged from 0.79 to 1.45 and there was no consistent pattern among the three groups; the changes were not statistically significantly different from baseline. Changes in measures of inflammation and pulmonary function tests were not different among the groups. Sulforaphane was well tolerated at both dose levels. CONCLUSION: Sulforaphane administered for four weeks at doses of 25 μmoles and 150 μmoles to patients with COPD did not stimulate the expression of Nrf2 target genes or have an effect on levels of other anti-oxidants or markers of inflammation. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01335971.
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A trial with patients suffering from COPD failed to observe any changes in alveolar macrophage and expression of antioxidant genes after sulforaphane.
“Trial with patients suffering from chronic pulmonary obstructive disease failed to observe any changes in alveolar macrophage and expression of antioxidant genes (Wise et al. 2016).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Wise et al. 2016
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“Several in vivo and in vitro studies have indicated that SFN can induce NRF2 pathway and promotes the downstream antioxidant genes (16, 21).”
BackgroundAntioxidants and Chronic Obstructive Pulmonary Disease
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“Previous studies also confirmed that NRF2 was a regulator of the AKR1C family via direct binding to the ARE located in the promoter regions of the AKR1Cs [49,63,64].”
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“A 4 week clinical trial of sulforaphane did not increase Nrf2 target gene expression, decrease markers of oxidative stress or improve lung function in patients with COPD [38].”
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“Sulforaphane has the active effect to the transcription factor Nrf2, which is reduced in the lungs of COPD patients, and the deficiency causes inflammation and corticosteroid resistance (Wise et al., 2016).”
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“Sulforaphane is tolerated well with participants, although some have reported gastrointestinal side effects during their treatment, such as heartburn, nausea, stomach pain, and diarrhea [11,12].”
BackgroundNew drugs under development for COPD
Bello, F. L., Hansbro, P. M., Donovan, C., Coppolino, I., Mumby, S. E., Adcock, I. M., & Caramori, G. (2020) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2020.1819982 · Cited by 23 · see citing works
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Sulforaphane and Brain Health: From Pathways of Action to Effects on Specific Disorders
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Peripheral Blood NRF2 Expression as a Biomarker in Human Health and Disease
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“NRF2 target genes HO-1 and GCLC were also decreased.”
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“For example, two trials reported no significant redox or anti-inflammatory changes after SFN supplementation (55,57) .”
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Transcription Factor NRF2 in Shaping Myeloid Cell Differentiation and Function
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Moringa isothiocyanate-1 inhibits LPS-induced inflammation in mouse myoblasts and skeletal muscle
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“The clinical trials that investigated the effects of sulforaphane on inflammatory markers are still not definitive [18, 41].”
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“However, three small sample size broccoli treatment RCTs did not demonstrate a reduction in IL-8, CRP and IL-6 in airway inflammation (Duran et al. 2016; Sudini et al. 2016; Wise et al. 2016).”
BackgroundLeukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy
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Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases
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Senotherapy for chronic lung disease
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“A clinical trial of sulforaphane in patients with COPD was negative, although target engagement was not demonstrated (Wise et al, 2016).”
Nrf2 Activation in Inflammatory Diseases: A Review of Natural and Synthetic Modulators
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“For instance, oral administration of compound did not signi fi cantly impact Nrf2 expression in patients with chronic obstructive pulmonary disease (COPD) [135].”
Novel Immunomodulatory Therapies for Respiratory Pathologies
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Role of Nuclear Factor Erythroid 2‒Related Factor 2 in Chronic Obstructive Pulmonary Disease
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“conducted a randomized, double-blind, placebo-controlled trial to determine whether oxidative stress, airway inflammation, and pulmonary function improve with the use of the Nrf2 inducer oral sulforaphane in 89 patients with COPD.(27) However, the effects of sulforaphane in patients with COPD were not demonstrated.”
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“Prior animal studies found that SFN treatment suppressed depression-like behaviors in mice (Wu et al., 2016; Zhang et al., 2017; Ferreira-Chamorro et al., 2018).”
ResultRibeiro, M. M., Cardozo, L., Paiva, B. R., Baptista, B. G., Fanton, S., Alvarenga, L., Lima, L. S., Britto, I. K., Nakao, L. S., Fouque, D. P., et al. (2023) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2023.08.008 · Cited by 11 · see citing works
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Delayed cortical bone healing due to impaired nuclear Nrf2 translocation in COPD mice
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Perioperative Heart-Brain Axis Protection in Obese Surgical Patients: The Nutrigenomic Approach
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“However, overall clinical efficacy of SFN is undetermined [24,25].”
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“Additionally, ITC (sulforaphane) displays no in vivo effect on Nrf-2 gene expression [40], which is in agreement with our result.”
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“However, in a clinical trial in which SFN was administered orally to these patients, such improvement was not observed [50].”
BackgroundTranscription inhibitors and inflammatory cell activity
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Oxidative stress in chronic disease: Mechanisms, therapeutic strategies, and future directions
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“Some compounds, such as sulforaphane, have shown clinical efficacy in treating diseases in other fields [175–177], although their application as HDAC inhibitors remains confined to oncology.”
- Authors
- Wise, R. A., Holbrook, J. T., Criner, G., Sethi, S., Rayapudi, S., Sudini, K. R., Sugar, E. A., Burke, A., Thimmulappa, R., Singh, A., Talalay, P., Fahey, J. W., Berenson, C. S., Jacobs, M. R., Biswal, S., & on behalf of Broccoli Sprout Extract Trial Research Group
- Affiliations
- Johns Hopkins University (US)
- Temple University (US)
- University at Buffalo, State University of New York (US)
- Corresponding author
- Wise, Robert A.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-11-10
- Volume
- 11
- Issue
- 11
- Pages
- e0163716
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5104323
- OpenAlex
- W2549382977
- Cited by
- 124
- References
- 32
- Citations by year
- 2026: 13 · 2025: 10 · 2024: 5 · 2023: 9 · 2022: 12 · 2021: 24 · 2020: 18 · 2019: 16 · 2018: 11 · 2017: 6
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Update notices
- correction (2017-03-28)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, public-domain)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Heart, Lung, and Blood Institute (5U01HL105569)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- sulforaphane, chronic obstructive pulmonary disease, Nrf2, oxidative stress, antioxidant gene expression, alveolar macrophages, bronchial epithelial cells, NQO1, heme oxygenase-1, AKR1C1, AKR1C3, airway inflammation, lung function, dietary supplementation
- MeSH terms
- Administration, Oral, Aged, Double-Blind Method, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Sulfoxides, Isothiocyanates, Oxidative Stress, Pulmonary Disease, Chronic Obstructive, NF-E2-Related Factor 2
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