INHIBITION OF METABOLIC-ACTIVATION OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE BY LIMONENE

Previous work by others shows that d-limonene (LIM) inhibits carcinoge n-induced lung tumorigenesis in mice and strongly suggests that LIM ca n inhibit the metabolic activation of nitrosamines such as 4-(methylni trosamino)-1-(3-pyridyl)-1-butanone (NNK). Thus, in the current study, the ability of LIM and other monoterpenes to inhibit the activation o f the tobacco-specific NNK was examined in murine pulmonary and hepati c microsomes after addition in vitro or administration in vivo. LIM in hibited the metabolic activation of NNK in both pulmonary and hepatic microsomes. Perillyl alcohol was a more potent inhibitor than LIM, whi le p-menth-1-ene was equipotent with LIM. After administration of LIM, limonene 1,2-oxide, or perillyl alcohol in vivo, significant inhibiti on of cytochrome P450-mediated metabolites (NNK N-oxide and HPB) was f ound at 1 and 4 fi after administration of monoterpene. These results indicate that LIM and other monoterpenes are effective inhibitors of N NK metabolic activation, and that other monoterpenes such as perillyl alcohol may be effective chemopreventive agents against NNK-induced lu ng tumorigenesis.