Phenethyl Isothiocyanate
What Is It?
Phenethyl isothiocyanate (PEITC) is a naturally occurring phytochemical derived from gluconasturtiin, a glucosinolate responsible for the pungency of cruciferous vegetables such as cabbage, kale, broccoli, and watercress. PEITC is produced by plants in response to mechanical or chemical stress via a reaction catalyzed by the enzyme myrosinase. This is because PEITC exhibits toxic activity against pathogens such as bacteria, fungi, and insects that threaten plant survival. Furthermore, the bacteria comprising our gut flora also produce myrosinase, which allows them to break down the glucosinolate we ingest from cruciferous vegetables. This process yields PEITC that can be absorbed into our tissues. While glucosinolates are inactive compounds, PEITC has recently garnered attention for its anti-inflammatory, antimicrobial, and – most prominently – anticancer properties. PEITC is being studied for its ability to counteract oxidative stress, activate carcinogen-fighting enzymes, and inhibit enzymes that produce carcinogenic compounds in the body.
What Are Its Other Names?
Phenethyl isothiocyanate is also known as phenylethyl isothiocyanate, 2-phenylethyl isothiocyanate, β-phenethyl isothiocyanate, β-phenylethyl isothiocyanate, or phenethyl mustard oil. Its IUPAC name is 2-isothiocyanatoethylbenzene. Watercress, or Nasturtium officinale, the main source of PEITC, is also known as yellowcress, and is a member of the Brassicaceae cabbage family.
What Foods Have It?
Food | PEITC content (mg/ 100 g) | Reference |
Watercress (best source of PEITC) | 52.6* | 6 |
Broccoli (next best source of PEITC) | 32.7* | 7 |
Brussels sprouts | 236.4** | 8 |
Radish | 160** | 8 |
Kale | 100** | 8 |
Turnips | 92.3** | 8 |
Cabbage | 64.4** | 8 |
Bok choy | 54.3** | 8 |
PEITC is predominantly found in cruciferous vegetables, including watercress, broccoli, Brussels sprouts, radish, kale, turnips, cabbage, and bok choy. It is responsible for the spicy and bitter taste attributable to these plants. However, the PEITC content attributable to the vegetables it is derived from is highly variable due to differences in food preparation. For instance, heating reduces the total PEITC content as isothiocyanates are easily destroyed by heat. In addition, the catalytic conversion by myrosinase produced by our microflora might be incomplete, lending to further variability in the bioavailability of PEITC in vivo. *These values represent the true bioavailability of PEITC in humans from watercress and broccoli consumption. **Note that the values reported for turnips and radish utilize total glucosinolate content as a proxy measurement for PEITC content as no data was found on the true bioavailability of PEITC in these vegetables. There are a couple different types of glucosinolates in these vegetables that yield a variety of compounds such as sulforaphane, benzyl isothiocyanate, and allyl isothiocyanate. The actual PEITC content will thus be somewhat lower than the above reported values. Additionally, PEITC has a bioavailability of 70% post-absorption – thus, the mass of PEITC that reaches our tissues is even lower.
What Are Its Main Benefits?
Reduction in risk of cancer development
Several epidemiological and clinical studies have demonstrated that PEITC consumption decreases the risk of developing breast, bladder, colorectal, gastric, and lung cancers. Most notable is the abundance of findings linking reduced lung cancer risk in smokers and PEITC intake. A phase 2 intervention study by the University of Minnesota demonstrated that oral PEITC intake led to significant increases in urinary levels of biomarkers of NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone) metabolism (NNK is a major tobacco-derived nitrosamine responsible for the carcinogenic properties of cigarettes). This is consistent with research indicating that PEITC inhibits the cytochrome enzymes that activate NNK, as well as another study that found elevated levels of NNAL-Gluc (a detoxification product of NNK) correlated with PEITC intake in smokers. Another case-control study noted a 43% lower risk in lung cancer when comparing groups with the highest and lowest intake of cruciferous vegetables, which is corroborated by the finding that higher urinary isothiocyanate content was associated with a reduced risk of lung cancer. One study found that women who consumed higher amounts of Brassica vegetables (1-2 servings a day) had a 20-40% lower risk of developing breast cancer. Moreover, Fowke et al. conducted a case-control study wherein they noted that controls had higher urinary isothiocyanate (ITC) content than breast cancer patients (2.31 µmol/mg creatinine vs 1.71 µmol/mg creatinine) and concluded an inverse relationship between ITC intake and breast cancer risk. Several studies have similarly found strong and significant correlations between decreasing bladder cancer risk and raw crucifer intake, but no associations were noted with cooked crucifer intake. In fact, consumption of raw broccoli was found to lead to a 57% reduction in disease-specific mortality with consumption of at least 1 serving of raw broccoli per month. With regards to reduction in colorectal cancer risk, high cabbage intake was linked to a reduced risk of colorectal cancer and a 57% reduction in risk was noted among high consumers of isothiocyanates in individuals with certain genotypes. A Netherlands cohort study also reported an inverse relationship between the consumption of brassica vegetables with the development of colon cancer.
Mitigation of Oxidative DNA Damage
One study involving 30 young smokers on a controlled diet of 250 g of broccoli (7 servings) per day found decreased DNA oxidation and hydrogen peroxide-mediated DNA strand breaks after just 10 days. Furthermore, in a randomized controlled trial involving women with histories of breast cancer, intake of around 14 cups per week of cruciferous vegetables for 3 weeks led to significantly reduced urinary biomarkers of oxidative stress (8-hydroxy-2’-deoxyguanosine), although this same association was not seen in individuals without breast cancer. It is important to note that while these oxidative stress studies did not directly involve PEITC ingestion, the compound has been heavily implicated as a factor in the protective role that cruciferous vegetables play in combatting oxidative damage, a key contributor to cancer development.
Halting Cancer Progression
In a 2023 randomized controlled trial, PEITC-fortified Nutri-Jelly administered to oral and oropharyngeal cancer patients led to significantly improved quality of life as well as enhanced progression-free survival time. Study group patients also had significantly improved BMIs compared to the placebo group and had higher average serum levels of p53 (a tumor suppressor protein), which is associated with stable tumor disease status. Note that since the epidemiological data above draws on information about total consumption of cruciferous vegetables, which are rich in a variety of phytochemicals and glucosinolates that yield several isothiocyanates, PEITC may not be the only player in their cancer-preventative action. Several confounding variables exist which may weaken the association between PEITC and cancer risk. Nonetheless, PEITC has been strongly demonstrated in cell culture and animal model studies to be an inhibitor of carcinogenesis, a promoter of cancer cell apoptosis (programmed cell death), and an inducer of carcinogen-metabolizing pathways as discussed in the “How Does It Work?” section of this article.
What Are Its Main Drawbacks?
One main drawback of using PEITC for cancer prevention is its instability and high sensitivity to heat. Intake of raw cruciferous vegetables provides 2-9 times the amount of isothiocyanates in humans compared to cooked crucifers, and no correlation was found between cancer risk and consumption of cooked crucifers. This limits the ways in which PEITC-rich foods can be prepared for consumption with the purpose of harnessing its cancer-preventing effects. Additionally, PEITC displays low bioavailability, which means that only a small fraction of consumed PEITC from the diet will reach its intended tissues and exert a protective effect. This is due to its low solubility, and the limited activity of intestinal myrosinase. Additionally, the average dietary intake of crucifers may not match the dose necessary for cancer prevention as demonstrated in cell or animal model studies. A 2016 randomized clinical trial reported mild gastrointestinal disorder symptoms (such as dry mouth, stomach-ache, and flatulence) when healthy adults were administered 10 mg PEITC in 1 ml olive oil 4 times/day for a week. The same researchers had conducted a previous study investigating the well-tolerated doses of PEITC and found that high intake of PEITC (120 mg) displayed some minor toxicity with low-grade diarrhea. Nonetheless, these were not considered serious side effects.
How Does It Work?
Through animal model and cell culture studies, PEITC has been demonstrated to exert cancer-preventative effects by inhibiting phase I enzymes which activate carcinogens, inducing the activity of phase II enzymes which metabolize carcinogens, blocking the pro-inflammatory NF-κB pathway, and promoting apoptosis in cancerous cells.
What Are Its Mechanisms of Action?
- Inhibition of Phase I Enzymes that Activate Carcinogens: Phase I enzymes consist of oxidases, such as cytochrome P450, which can activate procarcinogens (inactive precursors to carcinogens). Usually, the metabolites of procarcinogen activation are further metabolized by phase II enzymes, but if these enzymes cannot keep up with phase I enzyme activity, carcinogens can exert harmful effects on body tissues. PEITC has been studied in relation to NNK, an important carcinogen in tobacco, and has been found to block its metabolic activation by phase I enzymes (measured via greater excretion of NNAL and NNAL-Gluc, biomarkers of NNK metabolism, as well as decreased levels of HPB, a biomarker of NNK activation). Further, a case-control study found decreased bioactivation of tobacco procarcinogens in individuals with high intake of cruciferous vegetables. Additionally, PEITC has been identified as an antagonist of the Ah receptor involved in the pathophysiology of cancer. The receptor normally regulates the activity of cytochrome P450 and quinone reductase, both of which are enzymes that play essential roles in the bioactivation of carcinogens, but PEITC can inhibit the receptor and thereby inhibit phase I enzyme activation.
- Induction of Phase II Enzymes: Phase II enzymes work to counter phase I enzymes – they metabolize carcinogenic compounds and prevent them from producing the cellular damage needed to trigger cancer development. A study on rats fed with PEITC found that it induced the activity of several phase II enzymes, including epoxide hydrolase (which detoxifies the epoxide intermediates of several carcinogens), glucuronosyltransferase (a crucial detoxifying enzyme), and sulfotransferase, which break down carcinogenic compounds in the body. Most notably, consumption of Brassica vegetables has been found to enhance the activity of glutathione S-transferase (GST), an important phase II enzyme which catalyzes the addition of glutathione to carcinogenic metabolites, allowing them to be excreted in the urine. This occurs as PEITC treatment enhances the activation of the antioxidant response element (ARE), which upregulates the gene expression of two other phase II enzymes, glucuronosyltransferase and epoxide hydrolase. One experiment additionally found that PEITC induced phase II liver enzymes which metabolize PhIP (a carcinogenic compound found in cooked meat), thereby reducing the levels of cancer-promoting chemically-bound combinations of PhIP and DNA.
- Blocking Pro-Inflammatory Pathways: Inflammation is chief among the driving factors of cancer development and progression, and it may be brought about by infection, autoimmune disease, cigarette smoking, and alcohol consumption. The NF-κB pathway is a key mediator of inflammatory processes, and heavily implicated in cancer pathogenesis. Treatment of raw murine macrophages with PEITC demonstrated a dose-dependent inhibition of lipopolysaccharide (produced by Gram negative bacteria)-induced secretion of pro-inflammatory and pro-carcinogenic signaling molecules such as nitric oxide (NO) and prostaglandin E2 (PGE2). Additionally, PEITC has been shown to inhibit the induction of pro-inflammatory mediators (such as iNOS) which are normally induced via the NF-κB pathway.
- Promoting Apoptosis: Apoptosis (programmed cell death) is a normal process in healthy cells. It is crucial in the elimination of aberrant cells, and it is carried out by proteins known as caspases. An inability to undergo apoptosis is a hallmark of cancer cells, as they either overexpress anti-apoptotic proteins or under-express pro-apoptotic ones. Thus, PEITC’s ability to induce apoptosis has made it an attractive compound for anticancer research. One cell culture study found that exposing prostate cancer cells to 10 µM of PEITC for 24 hours led to a 56% and 44% decrease in expression of anti-apoptotic proteins (Bcl-2 and Bcl-XL), as well as an increase in the cleavage of several procaspases (pro-caspase 3, 8 and 9) to form active caspases which are involved in apoptosis. Furthermore, another study found that PEITC reversed cancer cell resistance to treatment with platinum, and a synergistic effect between PEITC and platinum produced increased drug-induced apoptosis and a lost ability of cancer cells to form cell colonies. This points to PEITC’s ability to counter treatment-resistant cancer cells, a phenomenon which has been observed in biliary tract cancer cells resistant to cisplatin, a well-known chemotherapeutic drug that induces apoptosis in cancer cells.
- Promoting Cell Cycle Arrest: Another key feature of cancer is uncontrolled cell growth, usually due to mutations in proto-oncogenes or in tumor suppressor genes. Proto-oncogenes play key roles in cell division, but when mutated they become oncogenes and cause excessive and uncontrollable cell division that may lead to cancer. On the other hand, tumor suppressor proteins, such as p53 and p21, play a critical role in slowing down cell division. If the genes from which they are transcribed become mutated, cells can also divide out of control and develop into cancer. PEITC has been shown to inhibit cell growth in HeLa cells (an important cell line for cancer research) in just 3 hours by 41-79% of control levels. Moreover, PEITC was associated with an over 80% reduction in levels of cyclin-dependent kinase 1 (Cdk1), a key protein in the proliferation of cancer cells, as well as an increase in levels of the beneficial molecule p21, which counteracts the cancer-promoting effects of Cdk1.
What Are Typical Doses and Durations?
Dosage The clinical studies that investigated the anticancer effects of PEITC have used doses ranging from 20 mg to 120 mg per day. Daily doses of 20 mg and 40 mg were well-tolerated (except for mild gastrointestinal symptoms observed with the latter dose), whereas the 120 mg dose (direct PEITC oral intake in olive oil carrier) was associated with mild toxicity and low-grade diarrhea. While the clinical trial utilizing the 20 mg dose (in 200 g of Nutri-Jelly) found potentially beneficial results in patients with oral or oropharyngeal cancer (as described in the “Benefits” section), the researchers that investigated a 40 mg daily dose deemed it too low a dosage for significant impact. Thus, a dosage of PEITC between 40 and 120 mg per day may be optimal for PEITC to exert notable anticancer effects. On another note, Terry et al. concluded that 1-2 daily servings of Brassica vegetables – which include watercress, cauliflower, horseradish, cabbage, and turnips – can lower the risk of developing breast cancer by 20-40%. Similarly, Wirth et al. noted that an intake of over 14 cups/ week of crucifers led to a significant decrease in urinary markers of oxidative stress in breast cancer patients, but not in those without breast cancer. One study aimed at quantifying the plasma PEITC levels after ingestion of 40 mg of PEITC found that peak plasma concentrations were detected between 3 and 5.5 hours. Another study directed at quantifying PEITC uptake via measuring a urinary metabolite of PEITC, PEITC-NAC, found that after four healthy volunteers consumed 30 g of watercress containing 9.79 mg/g of gluconasturtiin, 4.6-10.2 mg of PEITC-NAC were detected, with peak excretion at 2-4 hours after ingestion, corroborating the findings of the aforementioned study. These in vivo levels have been deemed effective doses for PEITC action by Chikara et al.. Duration The clinical trials on PEITC administered treatment for a variety of durations, ranging from 1 week to 2 or 3 months. In all cases, it was well-tolerated. The data is generally sparse on the appropriate dosage and duration of PEITC needed for significant effects in the body, especially with relevance to dietary forms of PEITC. More research is needed to conclusively define the optimal dosage and duration of PEITC intake for statistically significant anticancer action.
Summary of Data
PEITC for Cancer Due to the newly emerging interest in PEITC as a cancer-preventative nutrient, only four randomized controlled trials have been identified in PubMed that investigated PEITC consumption and its association with cancer prevention or treatment. The data from the trials is summarized below.
Cancer Type | Effect Investigated | General Effect (% based on the number of studies with positive or negative results) | Evidence (number of studies, participants) |
Oral & Oropharyngeal | Treatment | 100% reported beneficial effects | 1; 72 patients with advanced stage oral or oropharyngeal cancer |
Lung | Prevention | 100% reported beneficial effects | 3; 161 adult smokers |
PEITC for Prevention of Oxidative DNA damage Two additional randomized controlled trials were identified in PubMed that investigated watercress, which is rich in the PEITC precursor gluconasturtiin, and its role in the modulation of detoxification enzymes and prevention of oxidative damage. The 2009 trial used data obtained from the 2007 trial – they are thus grouped into one row in the detailed trial study notes, linked below.
General Effect (% based on number of studies with positive or negative effects) | Evidence (number of studies, participants) | |
Oxidative DNA Damage | 50% reported beneficial effects | 2 studies total; the 2007 human trial involved 60 healthy adults, half of which were smokers, and found significantly reduced oxidative DNA damage and increased levels of plasma antioxidants. The 2009 trial, however, found little effect on gene expression of detoxification enzymes in peripheral blood mononuclear cells |
📄 Detailed Phenethyl Isothiocyanate human clinical trial study notes analyzed by Anticancer.ca
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About This Article
First Published | November 3, 2023 |
Last Updated | November 3, 2023 |
Author | Adriana Goraieb |
Editor | Adin Aggarwal |
Reviewer and Supervisor | Kenneth W. Yip |
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