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


CONCLUSIONS
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.


BACKGROUND
Clinicaltrials.gov: NCT01335971.
Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
Robert A
RA
Wise
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
Janet T
http://orcid.org/0000-0002-0899-2345
JT
Holbrook
Temple University, Philadelphia, Pennsylvania, United States of America.
Gerard
G
Criner
University at Buffalo, SUNY and VA WNY Healthcare system, Buffalo, New York, United States of America.
Sanjay
S
Sethi
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
Sobharani
S
Rayapudi
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
Kuladeep R
KR
Sudini
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
Elizabeth A
EA
Sugar
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
Alyce
A
Burke
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
Rajesh
R
Thimmulappa
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
Anju
A
Singh
Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
Paul
P
Talalay
Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
Jed W
JW
Fahey
University at Buffalo, SUNY and VA WNY Healthcare system, Buffalo, New York, United States of America.
Charles S
CS
Berenson
Temple University, Philadelphia, Pennsylvania, United States of America.
Michael R
MR
Jacobs
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
Shyam
S
Biswal
D000284:Administration, Oral; D000368:Aged; D004311:Double-Blind Method; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D017879:Isothiocyanates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D013454:Sulfoxides
D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D013454:Sulfoxides; C016766:sulforaphane