2-Phenethyl Isothiocyanate, Glutathione S-transferase M1 and T1 Polymorphisms, and Detoxification of Volatile Organic Carcinogens and Toxicants in Tobacco Smoke

Abstract

Cigarette smoke contains relatively large quantities of volatile organic toxicants or carcinogens such as benzene, acrolein and crotonaldehyde. Among their detoxification products are mercapturic acids formed from glutathione conjugation, catalyzed in part by glutathione S-transferases (GST). A randomized phase 2 clinical trial with a crossover design was conducted to evaluate the effect of 2-phenethyl isothiocyanate (PEITC), a natural product formed from gluconasturtiin in certain cruciferous vegetables, on the detoxification of benzene, acrolein, and crotonaldehyde in 82 cigarette smokers. Urinary mercapturic acids of benzene, acrolein and crotonaldehyde at baseline and during treatment were quantified. Overall, oral PEITC supplementation increased the mercapturic acid formed from benzene by 24.6% (P=0.002) and acrolein by 15.1% (P=0.005), but had no effect on crotonaldehyde. A remarkably stronger effect was observed among subjects with the null genotype of both GSTM1 and GSTT1: in these individuals PEITC increased the detoxification metabolite of benzene by 95.4% (P<0.001), of acrolein by 32.7% (P=0.034), and of crotonaldehyde by 29.8% (P=0.006). In contrast, PEITC had no effect on these mercapturic acids in smokers possessing both genes. PEITC had no effect on the urinary oxidative stress biomarker 8-iso-prostaglandin F2α or the inflammation biomarker prostaglandin E2 metabolite. This trial demonstrates an important role of PEITC in detoxification of environmental carcinogens and toxicants which also occur in cigarette smoke. The selective effect of PEITC on detoxification in subjects lacking both GSTM1 and GSTT1 genes supports the epidemiological findings of stronger protection by dietary isothiocyanates against the development of lung cancer in such individuals.

The Role of Cruciferous Vegetables and Isothiocyanates for Lung Cancer Prevention: Current Status, Challenges, and Future Research Directions

“…Another finding that needs in vivo clarification is that PEITC can covalently modify the cysteine side chains of GST in vitro and in silico, which irreversibly inhibit the enzymatic activity of GST . Based on the in vitro finding, PEITC consumption should decrease, rather than increase, urinary concentrations of mercapturic acid metabolites of benzene, as observed in vivo by Yuan et al . Although a limited number of clinical trials used endpoints relevant to lung carcinogenesis to date, we found two trials in ClinicalTrials.gov that proposed to measure indicators of pulmonary inflammation, dysplasia, proliferation, or apoptosis, which would help further elucidate potential effects of ITCs for lung cancer prevention.…”

“…A limitation of many clinical trials is the small sample size, which limits investigators’ ability to detect statistically significant group differences, account for effect modification as well as result reporting. For example, the Minnesota study was not designed to adequately evaluate effect modification by GST genotypes, as the sample size in genotype groups was small (19–63 participants per group). In comparison, the sample size in the Qidong study was adequate (46–74 participants per group).…”

Mechanisms Underlying Biological Effects of Cruciferous Glucosinolate-Derived Isothiocyanates/Indoles: A Focus on Metabolic Syndrome

“…A study conducted among smokers showed that watercress consumption promotes a higher excretion of glucuronidated nicotine in urine indicating activation of the phase II enzyme UDP-glucuronosyltransferase (UGT) ( 80 ). Most recently, Yuan et al, in a randomized, placebo-controlled, double-blind study conducted among smokers found a greater excretion of the mercapturic acids of benzene and acrolein (substances of tobacco smoke) in urine after oral administration of PEITC for 5 days ( 81 ). In addition, human polymorphisms for the GST gene that affect their activity have been described ( 82 ).…”

Isothiocyanates: Translating the Power of Plants to People

“…In a recent study in which smokers were administered PEITC (10 mg, 4 times a day), the PEITC arm reduced metabolic activation of NNK, one of the most potent lung carcinogens present in cigarettes by 7.7% [54]. Larger increases in rates of excretion of detoxication metabolites (often mercapturic acids) of combustion pollutants such as benzene and aldehydes were observed following PEITC intervention [55] (Figure 2). Similar trends in modulating metabolism of air pollutants by broccoli sprout beverages had been observed in our group in two previous trials.…”