Environmental Factor, March 2011, National Institute of Environmental Health Sciences
Kensler discusses bench to tea-time research on Nrf2
By Jeffrey Stumpf
Kensler enjoyed audience reaction, as he described the strange brew his team tested in people living in a part of China with a very high incidence of liver cancer. (Photo courtesy of Steve McCaw)
NIEHS Visiting Fellow Deepa Sambandan, Ph.D., foreground, was lecture host. Sambandan is a trainee in the LMG Environmental Genomics Group, headed by Principal Investigator Doug Bell, Ph.D. (Photo courtesy of Steve McCaw)
NIEHS Principal Investigator Leping Li, Ph.D., was one of several Chinese scientists who attended the talk. (Photo courtesy of Steve McCaw)
Bell, above, was one of several LMG principal investigators who joined their trainees for Kensler's presentation. (Photo courtesy of Steve McCaw)
During his guest lecture at NIEHS Feb. 7, toxicologist Thomas Kensler, Ph.D., provided a new twist to the age-old axiom about eating your vegetables. Invited by Laboratory of Molecular Genetics (LMG) trainees, the University of Pittsburgh and Johns Hopkins University professor discussed the molecular and culinary implications of his research on Nrf2.
Kensler(http://www.pharmacology.us/Faculty/ThomasKensler) , who is a project leader on an NIEHS grant(http://tools.niehs.nih.gov/portfolio/index.cfm?action=portfolio.grantdetail&grant_number=P01ES006052), described his progress on studies that identified chemopreventive environmental agents, including sulforaphane, a chemical that is isolated from cruciferous vegetables such as broccoli.
A variety of stresses are involved in carcinogenesis, including metabolic stress, oxidative stress, and DNA damage. Transcription factors, such as Nrf2, induce the expression of proteins that protect the cell. Kensler discussed how inducing Nrf2 provides protection against diseases and suggested that Nrf2 is a potential prophylactic target.
Nrf2 expression increases only in response to environmental stresses. Kensler explains that the key to regulating Nrf2 is a complex between Keap1 and the ubiquitin ligase system that targets proteins for degradation. Under normal circumstances, Keap1 binds to Nrf2 and promotes the quick degradation of Nrf2. Environmental agents such as reactive aldehydes, as well as chemopreventive agents such as sulforaphane disrupt, Keap1, thereby preventing the destruction of Nrf2 and triggering the induction of protective genes.
Nrf2 pathway's three-tiered approach to damage: Prevention, control, repair
Kensler explained the importance of Nrf2 in disease prevention using the example of its inhibition of aflatoxin-induced liver tumors in rats. Nrf2 activates glutathione S-transferases that are used to detoxify aflatoxin. In mice without Nrf2, damage by aflatoxin increased along with sensitivity to carcinogenesis. Alternatively, reducing the amounts of Keap1 increased Nrf2 and was chemoprotective.
In addition to prevention, Kensler showed evidence that Nrf2 activates the pathway involved in removing DNA damage that occurs because of UV or oxidative damage. Nrf2 also induces proteins that increase proliferation of liver cells when tissue needs to be repaired.
Reducing cancer risk with broccoli? Clinical trials are brewing
The fact that the Nrf2-inducing chemical, sulforaphane, is in broccoli sprouts begs an obvious question. How much broccoli must someone eat to mimic the protection against carcinogenesis demonstrated in the lab? "Depending on the variety of broccoli, about 500 grams," Kensler explained. "It's about one head of broccoli, which is too much to consistently eat in a day."
Kensler and his colleagues offered a possible alternative - broccoli tea. The sprouts contain all of the glucoraphanin, the precursor to sulforaphane, in the plant, making it possible to be brewed into a tea and to provide a more practical method of ingestion.
To test the potential protective effects of broccoli tea, Kensler is leading a clinical trial in Qidong, a Chinese city where liver cancer is 25-fold more prevalent than in the population only 100 kilometers away. In addition to hepatitis B, exposure to aflatoxin-contaminated food is a major cause of liver cancer.
Volunteers in the clinical trials drank broccoli tea in a controlled tea house, and despite a bitter bite to the brew, there was 100 percent compliance. Measures in the urine excreted from the volunteers indicated that there was an average 50-fold increase in uptake of sulforaphane, but this amount varied among people.
Although early results showed only mild decreases in DNA damage, people with greater uptake of sulforaphane had fewer DNA damage adducts. This finding provides hope for the future of food-induced chemoprotective therapies, especially in poorer regions.
"When one thinks about broad-based intervention in Qidong, China or sub-Saharan Africa and other areas endemic for liver cancer, efficacy is clearly very important, but what is more important are the factors of cost, practicality, and tolerability," Kensler stated. "Using Western-based approaches and interventions are not going to work in those populations."
(Jeffrey Stumpf, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Mitochondrial DNA Replication Group.)