Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial

Abstract

BackgroundCOPD 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).MethodsThis 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.ResultsBetween 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.ConclusionSulforaphane 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 RegistrationClinicaltrials.gov: NCT01335971.

Targeting oxidant-dependent mechanisms for the treatment of respiratory diseases and their comorbidities

“…The Nrf2 activating molecule sulforaphane improves phagocytosis of bacteria in alveolar macrophages of patients with COPD [37]. 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]. The Nrf2 activator dimethyl fumarate (BG-12), which is approved in the US for the treatment of multiple sclerosis [39] is undergoing investigation in an inhaled microparticulate powder formulation for the treatment of respiratory disorders [40], but currently no clinical studies are underway in COPD or IPF [41].…”

The Role of Brassica Bioactives on Human Health: Are We Studying It the Right Way?

“…Within the short-term studies (Table S1), we found two documents on prostate [39] and melanoma [40], three papers on respiratory pathologies [41][42][43], and one on type 2 diabetes [44]. The main limitation observed in these studies is the length or duration of the study, of 1 month or less, because the validity of the data in terms of changes in bioavailability of the intake of compounds could be acceptable, but for the evaluation of data from tissues, the time of exposition is too low.…”

“…The work of Wise et al [42], compared to the previous one, increased the time of intervention, but again used a supplement-capsules with different concentrations of SFN. The pathology under study was chronic obstructive pulmonary disease (COPD), and in both cases, asthma and COPD were obstructive conditions.…”

The Role of Cruciferous Vegetables and Isothiocyanates for Lung Cancer Prevention: Current Status, Challenges, and Future Research Directions

“…For exposure indicator, urinary glutathione conjugates of ITCs are usually used but those have to be collected within 12 h to achieve a quantifiable range. Many of the “proof‐of‐concept” studies could not demonstrate that sufficient ITCs were absorbed to induce molecular targets in a threshold or dose‐response manner, future studies need to optimize methods for quantification of exposure. In regard to early response indicators, they need to be linked to dietary compounds through biological mechanisms as well as to the cancer endpoint.…”