COMPLETE INHIBITION OF ETHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE-INDUCED RAT LUNG TUMORIGENESIS AND FAVORABLE MODIFICATION OF BIOMARKERS BY PHENETHYL ISOTHIOCYANATE

Phenethyl isothiocyanate (PEITC), which occurs in certain cruciferous vegetables, was tested for its ability to inhibit lung tumorigenesis i n rats induced by the tobacco-specific nitrosamine 4-(methylnitrosamin o)-1-(3-pyridyl)-1-butanone (NNK) in a study involving virtually lifel ong administration of both compounds. In addition, two biomarkers of N NK metabolism [4-hydroxy-1-(3-pyridyl)-1-butanone-releasing hemoglobin adducts and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glu curonide in urine] were quantified in randomly selected rats during th e course of the study. The rats were assigned to groups as follows: NN K, 2 ppm in drinking water, 60 rats; NNK, 2 ppm in drinking water and PEITC, 3 mu mol/g NIH-07 diet, 60 rats; PEITC, 3 mu mol/g NIH-07 diet, 20 rats; and untreated controls, 20 rats. NNK was added to the drinki ng water for 111 weeks and PEITC to the diet for 1 prior to NNK admini stration and then throughout the 111-week course of treatment. There w ere no significant differences in body weights or survival among the g roups. There were no significant effects of PEITC on blood chemistry o r hematology. NNK induced lung tumors (adenoma and/or adenocarcinoma) in 70% of the rats. In the group treated with NNK plus PEITC, 5% of th e rats had lung tumors, which was not different from that of control r ats. PEITC also appeared to inhibit progression of benign to malignant pancreatic tumors. At intervals during the study, blood was withdrawn from selected rats, and 4-hydroxy-1-(3-pyridyl)-1-butanone-releasing hemoglobin adducts, which are formed upon metabolic activation of NNK, were quantified. The hemoglobin adducts were significantly repressed throughout the study in the rats treated with NNK plus PEITC compared to those treated with NNK. The 24-h urine sample of several rats was a nalyzed for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and 4-(methy lnitrosamino)-1-(3-pyridyl)-1-butanol glucuronide. A 4-6-fold increase in the sum of these metabolites was observed in the rats treated with NNK plus PEITC compared to those treated with NNK. This is also consi stent with inhibition of metabolic activation of NNK by PEITC. Collect ively, the results of this study provide strong evidence for the effic acy of PEITC as a chemopreventive agent against NNK-induced pulmonary carcinogenesis in rats and indicate that two biomarkers of NNK metabol ism, measurable in tobacco consumers, can be modulated in a predictabl e way by PEITC administration.