Mechanisms of Inhibition of Tobacco-Specific Nitrosamine-Induced Lung Tumorigenesis in A/J Mice

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The mechanisms of inhibition by arylalkyl isothiocyanates and green tea polyphenol of lung tumorigenesis caused by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were investigated. Our previous studies showed that pretreatment of A/J mice with phenethyl isothiocyanate (PEITC) inhibited the formation of lung tumors induced by NNK. However, PEITC's lower homologues, phenyl isothiocyanate (PITC) and benzyl isothiocyanate (BITC), were inactive. These results agreed with their effects on the formation of lung O6-methylguanine (O6-mG), a critical lesion in lung tumorigenesis resulting from the metabolic activation of NNK. We further tested a number of newly synthesized longer alkyl chain arylalkyl isothiocyanates for their inhibitory activities in A/J mice treated with NNK. The results showed that the potency of inhibition by arylalkyl isothiocyanates increased as the chain length increases. Treatment of mice with PEITC and BITC in the diet subsequent to NNK treatment had little effect on the formation of lung tumor induced by NNK These results are consistent with the mechanism that inhibition of lung tumorigenesis by arylalkyl isothiocyanates is due largely to the inhibition of enzymes which activate NNK In contrast to arylalkyl isothiocyanates, green tea and its major polyphenol, (-)-epigallocatechin gallate (EGCG), inhibited lung tumor formation in NNK-treated mice but exerted little effect on the formation of O6-mG in lung DNA. These results suggest that one or more DNA lesions other than methylation are involved in NNK lung tumorigenesis. We examined whether free radical-mediated oxidative DNA damage is induced in NNK-treated mice by measuring 8-hydroxydeoxyguanosine (8-OH-dG) formation. A dosedependent increase of this lesion in lung was seen in NNK treated mice. These results provide the first direct evidence of oxidative DNA damage by a nitrosamine. Consistent with their ability to inhibit lung tumor formation by NNK, the increase of oxidation in DNA by NNK was suppressed by treatment with green tea extract or its EGCG. These results support the involvement of free radical damage in NNK lung tumorigenesis as well as the role of green tea and its polyphenol as antioxidants in inhibition of the NNK-induced lung tumorigenesis in A/J mice.