Upon entry into the mammalian cell, sulforaphane is conjugated with GSH in a GST-catalyzed reaction, entering the mercapturic acid pathway (Scheme 1e). The glutathione conjugate of sulforaphane is subjected to a series of sequential conversions catalyzed by γ-glutamyltranspeptidase (γGT), followed by cysteinylglycinase (CGase), and N-acetyltransferase (NAT). The final product is the N-acetylcysteine conjugate of sulforaphane (mercapturic acid). In addition, sulforaphane can undergo an interconversion to erucin [1-isothiocyanato-4-(methylthio)butane], which is then metabolized in an identical manner to that for sulforaphane [48,49].
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Sulforaphane and its metabolites (dithiocarbamates) can be quantified collectively by cyclocondensation with 1,2-benzenedithiol, with sensitivity in the picomolar range [50]. This highly sensitive, simple and convenient method has been widely used to measure the levels of sulforaphane and its metabolites in blood, plasma, urine and tissues following sulforaphane administration to rodents and humans. The use of this method revealed that sulforaphane crosses the placental barrier based on detection of dithiocarbamates in embryos 2 h post-treatment of pregnant mice with a single (5 μmol) dose of sulforaphane [51]. In addition, methods have been developed to analyze the individual metabolites following their separation by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) [52,53]. Furthermore, the use of mass spectrometry coupled with stable isotope-labeled internal standards of sulforaphane [1-isothiocyanato-4-methyl-sulfinyl(1,1,2,2,3,3,4,4-2H8)butane] and its corresponding mercapturic acid pathway conjugates allows for quantitative, precise, sensitive, and specific analysis of sulforaphane and its metabolites [54].
With these analytical tools in hand, a number of pharmacokinetic studies have been conducted in rodents and humans. Thus, following oral administration of an exceedingly high dose of 150 μmol sulforaphane to 10-week-old female Sprague'Dawley rats, the concentration of dithiocarbamates in the plasma of the animals increased rapidly reaching a peak (Cmax) of 60 μM 1 h after dosing, with area under the concentration curve (AUC) of 491 h μmol/L, elimination constant (Kel) of 0.1 h'1, and elimination half-life of 6.7 h [55]. Similarly, following oral administration of 200 μmol broccoli sprout isothiocyanates to four healthy human volunteers, the peak plasma dithiocarbamate concentration (Cmax) was 1.91 ± 0.24 (0.943'2.27) μM 1 h after dosing, with half-life of 1.77 ± 0.13 h, and clearance of 369 ± 53 mL/min [56]. A study in 20 participants administered 200 μmol sulforaphane as sulforaphane-rich powder in capsules reported a Cmax of 0.7 ± 0.2 µM at 3 h, with a half-life of 1.9 ± 0.4 h for elimination of sulforaphane equivalents measured by mass spectrometry [57]. Another pharmacokinetic study, in which a single dose of broccoli soup delivering the equivalent of either 16 μmol or 52 μmol of sulforaphane was administered, reported Cmax of 2.2 ± 0.8 µM and 7.3 ± 2.9 µM at 1.5 h and 2 h for the low and the high dose, respectively [53]. A double-blinded, randomized crossover trial with broccoli soups (prepared from plants with increased glucoraphanin content) delivering a single dose of 84, 280, or 452 μmol of glucoraphanin documented peak plasma concentrations (Cmax) of 0.17 ± 0.12, 0.37 ± 0.26, and 0.61 ± 0.40 μM, respectively [52]. Another study reported plasma dithiocarbamate levels of 0.92 ± 0.72 μM and mean epithelial-/stromal-enriched breast tissue dithiocarbamate concentration of 1.45 ± 1.12 and 2.00 ± 1.95 pmol/mg tissue for the right and the left breast, respectively in eight healthy women undergoing reduction mammoplasty who had received a single dose of a broccoli sprout preparation delivering 200 μmol sulforaphane 1 h prior to surgery [55].
In a double-blind randomized placebo-controlled trial in men presenting for prostate biopsy, plasma levels of 0.12 µM of sulforaphane and its metabolites were detected after an intervention period of 4'8 weeks with two daily doses of 100 μmol sulforaphane administered 12 h apart [58]. Isothiocyanate levels of 2.2'µM and 500'nM were detected in the plasma and synovial fluid, respectively of patients with osteoarthritis undergoing knee replacement surgery following consumption of glucosinolate-rich diets for 2 weeks [59].
A study in healthy subjects who received single oral doses of broccoli sprout extracts containing the equivalent of 111 µmol of glucosinolates or isothiocyanates showed cumulative urinary dithiocarbamate excretion of 88.9 ± 5.5 μmol and 13.1 ± 1.9 μmol for the isothiocyanate and the glucosinolate preparation, respectively [60]. This study further revealed that for the isothiocyanate preparation, excretion was consistent and linear over a 25'200 μmol dose range, whereas for the glucosinolate preparation, excretion was highly variable among individuals. These observations are in close agreement with results from a randomized, placebo-controlled, double-blind Phase I clinical trial, in which isothiocyanate (25 μmol)- or glucosinolate (25 μmol or 100 μmol)-rich preparations were orally administered to three cohorts of three healthy human subjects at 8-h intervals for 7 days; one other subject in each cohort received placebo [61]. Notably, this study showed no evidence of clinically significant adverse events based on 32 types of hematology and chemistry tests, including liver (transaminases) and thyroid (TSH, T3, and T4) function tests. In agreement, a recent analysis of biochemical parameters of thyroid function in serum collected from 45 female volunteers that had participated in a randomized clinical trial revealed no alterations compared to baseline following an intervention for 12 weeks with a broccoli sprout beverage containing a combination of 40 μmol sulforaphane and 600 μmol of glucoraphanin [62].
The finding that compared to isothiocyanates, oral administration of glucosinolates results in lower bioavailability, slower elimination, and greater inter-individual variation in excretion was further strengthened by a larger (50 participants) crossover clinical trial that involved 5-day baseline period followed by daily administration of broccoli sprout beverages delivering either glucosinolates or their corresponding isothiocyanates for 7 days, 5-day washout period, and 7-day administration of the opposite intervention [63]. Using fecal sample collections from five subjects with high 24-h urinary excretion profiles ('high converters') and five subjects with low excretion profiles ('low converters'), it was found that ex vivo, the degradation of glucoraphanin was greater in cultures of fecal bacteria derived from the 'high converters' in comparison to the 'low converters' [64]. These observations are consistent with earlier work showing that mechanical cleansing or antibiotic treatment greatly reduce the glucosinolate conversion in healthy human subjects [26] and indicate that the gastrointestinal microflora represents a critical factor in determining the extent of gl ucosinolate hydrolysis. In addition to the inter-individual variations, there are also diurnal variations in the conversion of glucosinolates to dithiocarbamates, whereby conversion is greater during the day [65]. By contrast, the conversion of isothiocyanates to dithiocarbamates is higher during the night.
Overall, in humans, sulforaphane is rapidly absorbed and eliminated with small inter-individual variations and typical urinary excretion of 70% to 90% of the dose. By contrast, the conversion of glucoraphanin is slow and with high inter-individual variations. The urinary excretion of sulforaphane metabolites following intervention with glucoraphanin-containing preparations typically range from 2% to 15% of the dose, being 1% to 45% at the extremes. The differences in inter-individual variations between sulforaphane and glucoraphanin make, at first glance, the use of sulforaphane much more attractive for the purposes of dose precision. However, in contrast to its stable glucosinolate precursor, sulforaphane is unstable, which has prompted the development of stabilized preparations, such as an α-cyclodextrin-encapsulated form of sulforaphane [66] and a stabilized version of pure plant-derived sulforaphane, known as Prostaphane® (Nutrinov, Noyal sur Vilaine Cedex, France). Alternatively, glucoraphanin-rich preparations containing active myrosinase have also been used [67,68]. As formulations differ in their bioavailability (which provides a possible explanation for the differences in pharmacokinetic parameters reported in the various human studies), the excreted amount of sulforaphane metabolites in the urine, and not the amount in the administered preparation, provides a more reliable measure of the actual dose [69].
Similar to the studies of the pharmacokinetics of sulforaphane, nearly all human studies addressing the pharmacodynamics of sulforaphane have used glucoraphanin- or sulforaphane-rich broccoli-based preparations. Although there is currently no direct evidence for specific target engagement by sulforaphane in humans, there is clear evidence for its pharmacodynamic action. Thus, increased levels of the Nrf2-target enzymes A-class GSTs and NQO1 have been reported in plasma [70] and saliva [71] of human subjects consuming cruciferous vegetables. In agreement, administration of glucoraphanin/sulforaphane-rich preparations to healthy volunteers resulted in increased mRNA or protein levels of NQO1 and GSTs in PBMC, skin punch biopsies, as well as in nasal and buccal scrapings [72,73,74,75,76].
Broccoli-based glucoraphanin/sulforaphane-rich preparations have been shown to accelerate the detoxication and excretion of potentially carcinogenetic food contaminants and air pollutants, offering a very attractive strategy for population-wide reduction in cancer risk due to unavoidable exposures to pollution. A cross-over clinical trial with 50 human volunteers, which was conducted in Qidong, China, found statistically significant increases of 20'50% in the urinary excretion levels of glutathione-derived conjugates of the air pollutants acrolein and benzene following consumption of sulforaphane- and/or glucoraphanin-rich broccoli sprout-derived beverages [77]. A subsequent 12-week placebo-controlled, randomized clinical trial involving 291 participants from the same area using broccoli sprout beverages containing a combination of 40 μmol sulforaphane and 600 μmol glucoraphanin confirmed and extended these findings by showing that the excretion levels of the glutathione-derived conjugates of benzene and acrolein were significantly increased, by 61% and 23%, respectively in the volunteers who received the broccoli sprout beverage compared with placebo [78]. Very recently, a randomized, placebo-controlled, multidose intervention trial of a broccoli sprout beverage, which was conducted in the same area of China, showed a dose-dependent excretion of the urinary metabolites of sulforaphane, and further found that a treatment regime with daily doses of 40 μmol sulforaphane and 600 μmol glucoraphanin for 10 days, resulting in an urinary excretion of '25 μmol sulforaphane metabolites per day, promotes the detoxication of benzene [69].
Global gene expression profiling to evaluate the transcriptional changes in the prostate of men at high risk for prostate cancer has revealed that consumption of broccoli-rich diets for 6- or 12 months associates with transcriptional changes in signaling pathways involved in inflammation and carcinogenesis in the prostate tissue [79,80]; importantly, these changes are dose-dependently attenuated in subjects receiving the glucoraphanin-rich diet [80]. Other pharmacodynamic effects of interventions with glucoraphanin/sulforaphane in humans include: Increase in the levels of reduced glutathione in brain [81], enhanced integration of fatty acid β-oxidation with TCA cycle activity [82], protection against skin erythema caused by exposure to ultraviolet radiation [83,84], reduction in plasma LDL-cholesterol [85], decrease in the levels of fasting blood glucose and glycated hemoglobin in obese patients with dysregulated type 2 diabetes [86], and improvements in social interaction, behavior, and verbal communication in young men with autism spectrum disorder [87]. Overall, although the precise molecular mediators are not always known, it is clear that interventions with glucoraphanin/sulforaphane-rich broccoli preparations in humans lead to diverse beneficial effects.
Sulforaphane is a natural plant compound derived from cruciferous vegetables, such as broccoli and Brussels sprouts.
It is known for its antioxidant, antimicrobial, and anti-inflammatory properties. As such, some research has looked at its potential health benefits, including cancer prevention and heart and kidney health.
In the United States, the Food and Drug Administration (FDA) does not regulate supplements the way it regulates prescription drugs. That means some supplement products may not contain what the label says. When choosing a supplement, look for independently tested products and consult a healthcare provider, registered dietitian nutritionist (RD or RDN), or pharmacist.
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What Is Sulforaphane?
Sulforaphane is a natural plant compound derived from cruciferous vegetables, such as broccoli, cauliflower, and kale.
Sulforaphane in cruciferous vegetables is present in a stored, inactive form called glucoraphanin. Glucoraphanin is converted to sulforaphane's active form by the enzyme myrosinase. This activation is triggered by chopping or chewing but can also be produced in the gut by certain bacteria.
Sulforaphane Benefits
Supplement use should be individualized and vetted by a healthcare professional, such as a registered dietitian nutritionist (RD or RDN), pharmacist, or doctor. No supplement is intended to treat, cure, or prevent disease.
Researchers have studied sulforaphane for its potential health effects on various conditions, including cancer prevention, diabetes, heart disease, kidney health, and autism.
May Help Prevent Cancer
Sulforaphane has chemoprotective properties. That means it helps stop carcinogens (cancer-causing substances) from impacting the body. In addition, it's anti-inflammatory. Inflammation can play a role in some types of tumor formation. Sulforaphane may benefit cancer prevention.
A randomized study of adults with pancreatic cancer undergoing chemotherapy was conducted. The researchers reported the survival rate was higher in the treatment group than in the placebo group at six months. However, the results were not statistically significant.
Research published in studied the effects of sulforaphane supplementation on prostate cancer progression. Participants ate broccoli soup with glucoraphanin. The test group had a dose-dependent reduction in prostate cancer progression.
In addition, a study looked at the association between cruciferous vegetable intake and specific tumor biomarkers. Researchers evaluated 54 people scheduled for breast biopsies after abnormal mammogram findings.
Cruciferous vegetable intake was associated with decreased cell growth in breast tissue. However, other compounds in broccoli may have contributed to these findings.
May Help Autism Symptoms
Some studies have reported sulforaphane increased improvements in behavior, communication, and social interaction.
A randomized trial in collaboration with researchers from China, Johns Hopkins, Columbia University, and more reported some improvements in autistic children who were given sulforaphane. The treatment was also reportedly well tolerated. However, the researchers suggested further study was needed given the differences between clinician and caregiver scores.
On the other hand, a study published in reported a lack of clinically significant changes using sulforaphane for children with autism.
Further research is needed.
May Improve Cardiovascular Disease
Because oxidative stress and inflammation are markers in cardiovascular disease, and sulforaphanes have antioxidant and anti-inflammatory properties, researchers have looked at their potential role in protecting against heart disease.
A paper reviewed how sulforaphane might be protective against cardiovascular disease. Clinical studies and animal experiments demonstrated that sulforaphane is potentially protective against heart diseases, including hypertension and atherosclerosis.
Evidence for this use is limited. Therefore, more research is needed.
May Help Insulin Resistance in Diabetes
Sulforaphane's role in maintaining healthy cells and genes has prompted some researchers to look at its potential role in diabetes and insulin resistance (when your body doesn't respond normally to the hormone insulin) and diabetes.
A randomized, double-blind study examined the effects of broccoli sprouts on insulin resistance in people with type 2 diabetes. Researchers analyzed glucose and insulin levels in 63 people who received a placebo or broccoli sprout powder for four weeks. Results showed a significant decrease in serum insulin concentration and resistance in those receiving 10 grams per day of broccoli sprouts.
May Boost Kidney Health
Preclinical research from suggests that sulforaphane may benefit kidney health. Research indicates sulforaphane may:
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The bulk of these studies were in animal models, so further research in humans is warranted.
Other Potential Uses
In addition to the above, people also use sulforaphane for other health conditions, though there are few quality human studies on these topics. These include:
What Are the Side Effects of Sulforaphane?
Your healthcare provider may recommend sulforaphane to reduce your risk of cancer, heart disease, or diabetes. However, consuming a supplement like sulforaphane may have potential side effects. These may be common or severe.
Common Side Effects
Sulforaphane is safe when consumed in plant forms, such as kale or broccoli. In supplement form, sulforaphane has minor, if any, side effects. The main side effects include digestive problems, such as gas and a bad aftertaste. (Broccoli in particular is likely to cause gas.)
Severe Side Effects
Some animal research indicates that high doses of sulforaphane could cause the following side effects associated with toxicity:
Though sulforaphane seems to be well tolerated with minimal side effects, there is insufficient quality research to know if it is safe to take by mouth as a medicine, especially in high doses and for long periods.
Precautions
Sulforaphane is safe during pregnancy and breastfeeding when eaten in whole food form, such as broccoli. However, whether it's safe when taken as a supplement during pregnancy and breastfeeding is unknown. Therefore, you should avoid taking the supplement if you are pregnant or breastfeeding or consult with a healthcare provider first.
In addition, sulforaphane may interfere with some anti-seizure medications, including Tegretol (carbamazepine).
Dosage: How Much Sulforaphane Should I Take?
There are no daily intake recommendations for sulforaphane, and supplement brands vary widely in how much they suggest taking.
Some animal studies have used a wide range of dosages, including 3'10 µmol/kg to >100 µmol/kg.
Although there is a wide availability of sulforaphane in supplemental form, more research is needed to determine the ideal dose, safety, and effectiveness. Always speak with a healthcare provider before taking a supplement to ensure that the supplement and dosage are appropriate for your individual needs.
What Happens if I Take Too Much Sulforaphane?
While there is no established upper limit for sulforaphane, some research has found evidence of toxicity at doses of 150 to 300 milligrams/kilogram of body weight (mg/kg).
Seek immediate medical care if you experience any of the severe side effects listed above.
Sources of Sulforaphane
Sulforaphane is widely available through cruciferous food sources. In addition, you can take it as a supplement.
Food Sources of Sulforaphane
Cruciferous vegetables are well known for their sulforaphane content, including:
Cooking foods seems to decrease the amount of sulforaphane in cruciferous vegetables, with raw vegetables having the highest levels of sulforaphane. According to one study, raw broccoli has 10 times more sulforaphane than cooked broccoli.
If you prefer your cruciferous vegetables cooked, steaming might have the least effect on sulforaphane levels. A study found that steaming broccoli for one to three minutes may be the best way to get the most sulforaphane when cooking, compared to microwaving and boiling.
Sulforaphane Supplements
Sulforaphane supplements are available in various forms, including:
They are often made from broccoli, broccoli seeds, or broccoli sprouts extract. Some sulforaphane supplement manufacturers also advertise their products as combined with myrosinase enzymes for enhanced absorption.
How to Store Sulforaphane
Store sulforaphane in a cool, dry place. Keep sulforaphane away from direct sunlight. Discard after one year or as indicated on the packaging.
Summary
Sulforaphane is a natural plant compound found in cruciferous vegetables and supplements. It is known for its antioxidant, antimicrobial, and anti-inflammatory properties. Some people take sulforaphane for health reasons, such as lowering their risk of cancer, heart disease, kidney conditions, and diabetes, or to treat moderate to severe autism symptoms. There is some evidence to support those uses, but the research is limited.
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