Inhibition of metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by limonene

Previous work by others shows that d-limonene (LIM) inhibits carcinogen-induced lung tumorigenesis in mice and strongly suggests that LIM can inhibit the metabolic activation of nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Thus, in the current study, the ability of LIM and other monoterpenes to inhibit the activation of the tobacco-specific NNK was examined in murine pulmonary and hepatic microsomes after addition in vitro or administration in vivo. LIM inhibited the metabolic activation of NNK in both pulmonary and hepatic microsomes. Perillyl alcohol was a more potent inhibitor than LIM, while p-menth-1-ene was equipotent with LIM. After administration of LIM, limonene 1,2-oxide, or perillyl alcohol in vivo, significant inhibition of cytochrome P450-mediated metabolites (NNK N-oxide and HPB) was found at 1 and 4 h after administration of monoterpene. These results indicate that LIM and other monoterpenes are effective inhibitors of NNK metabolic activation, and that other monoterpenes such as perillyl alcohol may be effective chemopreventive agents against NNK-induced lung tumorigenesis.