Benzyl isothiocyanate (BITC) inhibits lung
tumorigenesis induced in A/J mice 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 compared in mouse lung and liver microsomes, 6 or 24h
after treatment with BITC or
PEITC. In lung, 6 h
after treatment, B[a]P-7, 8-diol and some other metabolites 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-treated mice, whereas it was substantially increased in mice treated with
PEITC. Effects on B[a]P metabolism in liver microsomes were generally modest. Conversion of B[a]P-7,8-diol to
mutagens by mouse liver microsomes was more strongly 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 in
DNA from mice treated with
isothiocyanates and B[a]P, and killed 2-120h later. 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 between the reduction of
BPDE-DNA AUC values by BITC versus
PEITC. The results of this study support the hypothesis that BITC inhibits B[a]P-induced lung
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.