Effects of benzyl and phenethyl isothiocyanate on P450s 2A6 and 2A13: potential for chemoprevention in smokers

Isothiocyanates have been shown to be potent inhibitors of carcinogenesis in animals exposed to a number of chemical carcinogens including the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In this study the effects of benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC), two naturally occuring isothiocyanates, on P450 2A6 and 2A13 were investigated. P450s 2A6 and 2A13 are thought to be the primary human P450 enzymes responsible for the in vivo metabolism of nicotine and NNK, respectively. In vitro, BITC and PEITC efficiently inhibited P450 2A6- and 2A13-mediated coumarin 7-hydroxylation. The inhibition of P450 2A6 and 2A13 by BITC was non-competitive with KI's of 4.1 and 1.3 microM, respectively. PEITC was a more potent inhibitor of both enzymes than BITC, with a KI of 0.37 microM for P450 2A6 and 0.03 microM for P450 2A13. P450 2A6-mediated metabolism of nicotine and P450 2A13-mediated alpha-hydroxylation of NNK were also inhibited significantly by these two isothiocyanates. Both BITC and PEITC were able to inactivate P450 2A6 and 2A13 in an NADPH-dependent manner potentially through the formation of adducts to the apoprotein. The potent inhibition of P450 2A6- and 2A13-mediated metabolisms together with the ability of BITC and PEITC to inactivate the enzymes suggests the possibility that these isothiocyanates could be developed as chemopreventive agents to protect smokers who are unwilling or unable to quit smoking against lung cancer.