EFFECTS OF ISOTHIOCYANATES ON TUMORIGENESIS BY BENZO[A]PYRENE IN MURINE TUMOR-MODELS

Previous studies have shown that benzyl isothiocyanate (BITC) inhibited lung tumorigenesis induced in A/J mice by benzo[a]pyrene (BaP), but other experiments using a somewhat different protocol demonstrated that phenethyl isothiocyanate (PEITC) had no effect on lung tumorigenesis induced by BaP in this strain. In contrast, PEITC but not BITC had been shown to inhibit lung tumorigenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice. Therefore, one goal of this study was to directly compare the chemopreventive activities of BITC and PEITC on BaP-induced lung tumorigenesis in A/J mice. In the same experiment we also compared the tumorigenic activities of BaP and NNK. Either BITC or PEITC was administered by gavage 15 min before gavage of BaP. This regimen was carried out three times at 2-week intervals, and the mice were sacrificed 26 weeks after the first treatment. As assessed by tumor multiplicity, BITC but not PEITC significantly inhibited lung tumorigenesis by BaP, whereas PEITC but not BITC significantly inhibited forestomach tumorigenesis. Comparison of the tumorigenic activities of NNK and BaP demonstrated that NNK was about ten times more potent than BaP as a lung tumorigen, while BaP but not NNK induced forestomach tumors. In a second set of experiments we evaluated the effects of isothiocyanates on the mouse skin tumor-initiating activity of BaP. The isothiocyanates tested were BITC, PEITC, 6-phenylhexyl isothiocyanate (PHITC) and a series of isothiocyanates structurally related to polynuclear aromatic hydrocarbons: 9-phenanthryl isothiocyanate (9-PhenITC), 9-phenanthrylmethyl isothiocyanate (9-PhenMeITC), 6-chrysenyl isothiocyanate (6-ChrysITC) and 6-benzo[a]pyrenyl isothiocyanate (6-BaPITC). None of the isothiocyanates inhibited tumor development by BaP, and three of them - PHITC, 9-PhenITC and 9-PhenMeITC - enhanced skin tumor multiplicity. Taken together with available literature data, the results of this study suggest that different isothiocyanates selectively inhibit cytochrome P450 enzymes involved in the metabolic activation or detoxification of BaP and therefore have differing effects on BaP tumorigenesis.