Effects of isothiocyanate alkyl chain-length on hamster liver cytochrome P-450 activity

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is metabolized by various isozymes of cytochrome P-450 present in microsomes. In this study, we examined the effects of the isothiocyanate homologues, phenyl isothiocyanate (PITC), benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC) and phenylpropyl isothiocyanate (PPITC) on the mutagenicity and in vitro metabolism of NNK by Syrian golden hamster liver microsomes and on the in vitro microsomal metabolism of testosterone. Each isothiocyanate compound inhibited N-oxidation and alpha-hydroxylation reactions of NNK that, except for PITC, correlated with an inhibition of microsomal-mediated mutagenicity of NNK in Salmonella typhimurium TA1535. Each isothiocyanate also inhibited cytochrome P-450-mediated hydroxylation reactions of the metabolism of testosterone. In general, the inhibitory potency of the isothiocyanates corresponded with the length of the alkyl chain of the compound. Our data support the ability of isothiocyanates to inhibit the activity of a number of isozymes of cytochrome P-450.