Effect of alkyl chain length on inhibition of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis and DNA methylation by isothiocyanates

This study was undertaken to evaluate the inhibitory effectsof benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC),3-phenylpropyl isothiocyanate (PPITC) or 4- phenylbutyl isothiocyanate(PBITC) on N-nitrosomethylbenzylamine (NMBA)-induced esophagealtumorigenesis in male Fisher 344 rats. Groups of 15 male ratswere fed modified AIN-76A diet or diet containing the four isothiocyanatesat concentrations of 2.5, 1.0 and 0.4 µmol/g diet for25 weeks. After two weeks, rats were administered 0.5 mg/kgNMBA S.C. once weekly for 15 weeks. Additional controls receivedmodified AIN-76A diet only or diet containing the high concentrationof isothiocyanates (2.5 µmol/g) only. No tumors were foundin any of the groups that were not administered NMBA. Rats treatedwith NMBA only developed 6.7±0.8 tumors/animal. Tumorincidences in rats treated with 2.5 and 1.0 µmol PEITC/gdiet, and with all three dietary concentrations of PPITC wereinhibited by 60/100% compared to controls. Tumor multiplicitieswere inhibited by 83–100% by PEITC or PPITC at all dietaryconcentrations tested. PPITC clearly had a stronger inhibitoryeffect on NMBA tumorigenesis than did PEITC. Compared to PEITCand PPITC, BITC and PBITC had little inhibitory effect on tumormultiplicity and no effect on NMBA tumor incidence. In general,the occurrence of preneoplastic lesions (acanthoses, hyperkeratose,leukoplakias and leukokeratoses) was inhibited in a similarmanner as tumor incidence and multiplicity, except that no experimentaldiet resulted in a significant reduction of the incidence ofacanthoses and hyperkeratoses. As with their effects on tumorigenicityand formation of premalignant lesions, the inhibitory effectsof the isothiocyanates on NMBA-induced DNA methylation 24 hafter administration followed the order: PPITC > PEITC >PBITC > BITC.