Effects of isothiocyanates on cytochrome P-450 1A1 and 1A2 activity and on the mutagenicity of heterocyclic amines.

In this study we investigated the effects of phenyl isothiocyanate (PITC), benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC) and phenylpropyl isothiocyanate (PPITC) on the mutagenicity of five heterocyclic amines, IQ, MeiQx, Trp-P-2, Glu-P-2 and PhIP in Salmonella typhimurium strain TA 98 in the presence of liver microsomes from male Syrian golden hamsters. In addition, the effects of these isothiocyanates on cytochrome P-450 1A1 and cytochrome P-450 1A2 activities were determined by measuring the deethylation and the demethylation of ethoxyresorufin (EROD) and methoxyresorufin (MROD) respectively. With the exception of Trp-P-2, all four isothiocyanates significantly inhibited HCA-induced mutagenesis in TA 98 at concentrations of 0.05 and 0.1 mumoles/plate. BITC was the only isothiocyanate tested that showed a dose-dependent inhibition of Trp-P-2-induced mutagenesis. These four isothiocyanates showed a dose-dependent inhibition of EROD activity and, with the exception, of BITC, of MROD activity also. This indicates that the inhibition of HCA-induced mutagenesis correlates with the inhibition of cytochrome P-450 1A1 and 1A2. These P450s are known to metabolically activate HCAs. The inhibitory effects of the isothiocyanates were greater toward HCA-induced mutagenesis in TA 98 than toward EROD and MROD activity. This indicates that the antimutagenic effects of PITC, BITC, PEITC and PPITC on HCA-induced mutagenesis in Salmonella typhimurium TA 98 involves more than the inhibition of cytochrome P-450 1A1 and 1A2 activity in hamster liver microsomes.