Diindolylmethane (DIM), a compound derived from phytochemicals found naturally in cruciferous vegetables, can stimulate multiple detoxification pathways in cells. Novel clinical studies by LPI investigator Dr. David Williams seek to determine how DIM can stop carcinogen exposure from leading to cancer.
Not everyone likes eating Brussels sprouts, including Dr. David Williams, the LPI Helen P. Rumbel Professor for Cancer Prevention. “I talk the talk,” Dr. Williams admits, “But it is hard for me to walk the walk, even with everything I know about the cancer-fighting properties of cruciferous vegetables.”
Members of the cruciferous vegetable family can have a strong flavor and odor; some people say they also have a bitter taste.
Yet there is some evidence that cruciferous vegetable intake is associated with a lower risk of certain types of cancers. Specific phytochemicals found in cruciferous vegetables may be responsible for this protection, leading many investigators to determine the exact mechanisms for this effect.
Dr. Williams focuses on Brussels sprouts and the phytochemical they can produce called diindolylmethane (often called DIM). While many cruciferous vegetables are considered a source of DIM, they do not produce DIM directly. Instead, DIM starts out as a compound called glucobrassicin in plant cells.
To form DIM, glucobrassicin must first react with an enzyme that is also present in the plant called myrosinase. This usually happens when the plant is damaged in some way. Crushing, chopping, blending, or chewing will work just as well to release the enzyme and start the reaction.
Once this happens, a compound called indole-3-carbinol is released and DIM can be produced.
DIM and indole-3-carbinol have been the subjects of investigation for many cancer studies. One important finding is that these indoles seem to stimulate cellular detoxification processes. It is thought that if detoxification systems are stimulated in advance of exposure to a carcinogen, cancer protection results.
The Williams laboratory focuses on preventing these exposures to carcinogens. Their early studies focused on exposures to fish, specifically trout. More recently, they used mice to demonstrate that dietary indoles (like DIM) in the maternal diet could protect offspring from developing cancer later in life.
Their hypothesis is as follows: Eating Brussels sprouts will protect from carcinogen exposures, as the DIM would prevent at least some of the cellular damage these toxins can cause. Put simply, DIM may be a carcinogen blocker. Now they are conducting the clinical studies to support this concept.
In order to do this, Dr. Williams first had to tackle a few logistics — feeding Brussels sprouts to people was the easy part. To see if the provided DIM stimulates detoxification of carcinogens, they needed to find a way to expose people to that toxin, track its fate in the body, and still make it safe.
Dr. Williams has decades of experience studying polycyclic aromatic hydrocarbons (also called PAHs). Products of burning organic material (e.g., coal, gasoline, or wood), PAHs are found in the environment in varying amounts but also in essentially all food we eat to some degree. They are present at highest levels in smoked and charcoal grilled foods, due to the proximity to burning materials. The most studied of these PAHs called benzo[a]pyrene (or BaP) is extremely common, but a known human carcinogen.
Although we are exposed to PAHs every day, it is not in a controlled way. From experience, Dr. Williams knew that the small doses of BaP they planned to use in their study (about 45 nanograms — the weight of a grain of pollen) were well below the estimated amount one gets from dietary sources every day. An adult living in the US can be exposed to 270-750 ng per day.
By comparison, the amount of carcinogen consumed by participants in this study was far below a person eating some wood smoked salmon or a charcoal grilled hamburger. To track these extremely small amounts of carcinogen, there is only one solution: Dr. Williams needed to use radioactive isotopes.
While this might sound alarming, it is in actuality quite innocuous. Small amounts of radioactivity are found everywhere in our daily lives. The food that we eat and the water we drink are full of radioactive isotopes of carbon and potassium that are abundant on our planet.
“To put this in perspective,” Williams explains, “The amount of radioactivity we are using is the equivalent to that found in five bananas and less than one percent of a dose that is given to patients to diagnose Helicobacter pylori infections.”
The radiation dose is measured at five nanocuries, roughly equivalent to a routine X-ray. However, to make sure that this exposure was safe to all participants, the National Institutes of Health, the Food and Drug Administration, and Oregon State University’s Institutional Review Board all reviewed and gave Dr. Williams permission to proceed with the study.
The advantages in using radioactive isotopes are quite clear to researchers: The labeling allows researchers to use very small quantities and still find them within the body. Radioisotopes provide extra mass to these molecules, allowing them to distinguish isotope-labeled products from unlabeled products — at least, with a little help from a particle accelerator.
Collaborators at Lawrence Livermore National Laboratory’s Center for Accelerator Mass Spectrometry have been working with the Williams lab for years to analyze plasma and urine samples from human volunteers. With their accelerator mass spectrometer technology (AMS), the sensitivity of measurements has dramatically increased. “AMS combined with radioisotopes gave us astounding levels of sensitivity,” says Dr. Williams, “Imagine the ability of detecting the equivalent of a single drop of blood in a volume the size of a small lake.”
In order to see the effects of DIM, each volunteer needs to consume the radiolabeled BaP alone and in a separate trial with the inclusion of Brussels sprouts or the DIM capsules. Metabolic products from the BaP are quantified, including any that associate with DNA, and the differences between the two trials will show exactly the effects of DIM — and the whole food from which the metabolites are derived — on carcinogen metabolism.
As Dr. Williams notes, “This is the first human trial to determine if a cruciferous vegetable, or a food-derived dietary supplement, can alter the risk from ingesting a known carcinogen at an environmentally relevant dose. To date, we have had to rely on risk assessment from data from animals dosed with 10,000 to 1 million times the exposures people face on a daily basis.”
This trial is currently underway and the details are found at clinicaltrials.gov under study number NCT03631667. We will have more insights to report from the study as it proceeds.
The health benefits of cruciferous vegetables likely stretch beyond DIM and sulforaphane. So even if you are not a big fan of Brussels sprouts in particular, broccoli, cabbage, or kale can be a healthful addition to your diet.
References
Hummel et al. Food and Chemical Toxicology 115 (2018) doi: 10.1016/j.fct.2018.03.003
Higdon et al. Pharmacological Research 55 (2007) doi: 10.1016/j.phrs.2007.01.009
Yu et al. Carcinogenesis 27 (2006) doi: 10.1093/ carcin/bgl072
