MECHANISM OF ENHANCEMENT OF ESOPHAGEAL TUMORIGENESIS BY 6-PHENYLHEXYLISOTHIOCYANATE

6-Phenylhexyl isothiocyanate (PHITC) enhances esophageal tumorigenesis induced by the carcinogen N-nitrosomethylbenzylamine (NMBA) in rats w hile its shorter chain analog, phenethyl isothiocyanate (PEITC), inhib its NMBA-induced esophageal tumorigenesis. A significant increase in O -6-methylguanine levels in esophageal DNA at 72 h after NMBA administr ation to rats pretreated with PHITC suggested that PHITC might enhance NMBA metabolic activation or inhibit DNA repair. To test this hypothe sis, groups of 20 rats were administered PEITC or PHITC at concentrati ons of 0, 1.0, or 2.5 mmol/kg in modified AIN-76A diet for 2 weeks. Th e esophagi were removed from rats, stripped, split, and maintained in HEPES buffered saline (HBS) for assays of NMBA metabolism (n=5 per gro up) or were snap frozen for DNA repair assays (n=15 per group). The pr incipal metabolites of NMBA produced by esophageal explants were: two unidentified peaks, benzyl alcohol (at 4 h only), and benzoic acid. Es ophageal explants from PEITC-treated animals showed a significantly de creased ability to metabolize NMBA as expected. PHITC-treated animals showed a slight inhibition in the formation of most NMBA-related metab olites, rather than an overall increase in NMBA activation. This inhib ition was less than that observed with PEITC. No inhibitory effects we re observed on O-6-alkylguanine transferase (AGT) activity in the esop hagi of rats treated with 1.0 mu mol/g or 2.5 mu mol/g PHITC. Thus, ef fects of PHITC on esophageal metabolism and DNA repair do not account for the enhancement of NMBA tumorigenicity by PHITC. (C) 1997 Elsevier Science Ireland Ltd.