Abstract 4347: A randomized phase 2 clinical trial of PEITC on detoxification of tobacco-specific and non-specific carcinogens and toxicants

Abstract

Abstract Abstract Background: Cigarette smoke contains the tobacco-specific lung carcinogen NNK and other carcinogens and toxicants. 2-Phenethyl isothiocyanate (PEITC), a natural product found as a conjugate in cruciferous vegetables, can inhibit the metabolic activation and lung carcinogenicity of NNK in rodents. Intake of a broccoli sprout beverage containing high levels of sulforaphane can increase urinary excretion of benzene and acrolein metaboites. Glutathione S-transferases (GST) catalyze the conjugation of carcinogens and toxicants with glutathione enhancing their urinary excretion, thus functional GST genotypes may modify the effect of PEITC. Methods. The goal of this randomized phase 2 clinical trial with a crossover was to determine if PEITC inhibits the metabolic activation of NNK and enhances the detoxification of benzene, acrolein and crotonaldehyde. Eighty-two smokers were completed the trial. The smokers smoked cigarettes containing deuterium labeled [pyridine-D4]NNK to allow measurement of metabolic activation. The subjects were randomly assigned to one of two arms: PEITC-placebo, or placebo-PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 ml of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. Three 24h urine samples were collected during each of the 2 treatment periods. The NNK metabolic activation ratio: [pyridine-D4]hydroxy acid/total [pyridine-D4]NNAL, and the mercapturic acids of benzene, acrolein and crotonaldehye in urine were quantified using validated LC-ESI-MS/MS methods. The linear mixed model with random effect was used to examine the PEITC effect. Results. Overall, PEITC treatment significantly reduced the NNK metabolic activation ratio by 7.7% (P = 0.023), and increased the detoxification metabolites of benzene by 24.6% (P = 0.002) and acrolein by 15.1% (P = 0.005), but had no effect on crotonaldehyde (5.5%, P = 0.148). PEITC had stronger effects in subjects with GST null genotype. PEITC reduced the NNK metabolic activation ratio by 15.6% (P = 0.039), and increased detoxification metabolites of benzene by 95.4% (P <0.001), acrolein by 32.7% (P = 0.034), and crotonaldehyde by 29.8% (P = 0.006) among the subjects with null genotype of both GSTM1 and GSTT1, but had no effect in those possessing both genes (Pinteraction < 0.05). Conclusion. The results of this trial demonstrate that PEITC inhibits the metabolic activation of NNK in smokers, and has a stronger effect on the detoxification of environmental carcinogens and toxicants such as benzene, acrolein, and crotonaldehyde. A more pronounced effect of PEITC in subjects lacking both GSTM1 and GSTT1 genes supports the epidemiological findings of stronger protection of dietary isothiocyanates against the development of lung cancer in such individuals. [Grant support: NCI R01CA122244]. Citation Format: Jian-Min Yuan, Jian-Min Yuan, Irina Stepanov, Sharon E. Murphy, Sharon E. Murphy, Renwei Wang, Steven G. Carmella, Heather H. Nelson, Heather H. Nelson, Dorothy Hatsukami, Stephen S. Hecht. A randomized phase 2 clinical trial of PEITC on detoxification of tobacco-specific and non-specific carcinogens and toxicants. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4347.