Effects of benzyl isothiocyanate and phenethyl isothiocyanate on benzo[a]pyrene metabolism and DNA adduct formation in the A/J mouse

Benzyl isothiocyanate (BITC) inhibits lung tumorigenesis induced in A/J mic e by benzo[a]pyrene (B[a]P), In contrast, phenethyl isothiocyanate (PEITC) does not. We tested the hypothesis that BITC inhibits B[a]P tumorigenicity in mouse lung by inhibiting DNA adduct formation, and compared the effects of BITC and PEITC, In mouse liver or lung microsomal incubations, BITC and PEITC inhibited formation of 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (B[a]P -7,8-diol) and some other B[a]P metabolites, The metabolism of B[a]P was co mpared in mouse lung and liver microsomes, 6 or 24h after treatment with BI TC or PEITC, In lung, 6 h after treatment, B[a]P-7,8-diol and some other me tabolites were inhibited by BITC and PEITC, However, 24 h after treatment, no inhibition of B[a]P-7,8-diol was observed in microsomes from BITC-treate d mice, whereas it was substantially increased in mice treated with PEITC, Effects on B[a]P metabolism in liver microsomes were generally modest. Conv ersion of B[a]P-7,8-diol to mutagens by mouse liver microsomes was more str ongly inhibited by BITC than PEITC, Effects on 7,8-dihydroxy-9,10-epoxy-7,8 ,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA adduct formation were evaluated i n DNA from mice treated with isothiocyanates and B[a]P, and killed 2-120h l ater. The area under the curve (AUC) for BPDE-DNA adducts in lung was 29.5% less (P = 0.001) in the BITC-B[a]P treated mice and 19.0% less (P = 0.02) in the PEITC-B[a]P mice than in the mice treated with B[a]P alone, Similar results were obtained in liver DNA, There were no significant differences b etween the reduction of BPDE-DNA AUC values by BITC versus PEITC, The resul ts of this study support the hypothesis that BITC inhibits B[a]P-induced lu ng tumorigenesis in A/J mice by inhibiting the metabolic activation of B[a] P to BPDE-DNA adducts, However, differences in BPDE-DNA adduct formation do not appear to explain fully the contrasting effects of BITC and PEITC on B [a]P-induced lung tumorigenesis.