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. Author manuscript; available in PMC: 2009 Jan 1.
Published in final edited form as: Chem Res Toxicol. 2007 Dec 4;21(1):160–171. doi: 10.1021/tx7002068

Figure 1.

Figure 1

Abstraction of the prochiral rear 4-hydrogen of NNK, catalyzed by mouse lung P450 2A5 (and possibly other P450s), is the requisite step which initiates a cascade of events leading to lung tumor formation in the A/J mouse. A single dose of 10 µmol of NNK induces about 10 lung tumors per mouse after 16 weeks in this model without the need for any exogenous tumor promoter or genetic manipulation (136). Deuterium labeling studies demonstrate that levels of O6-methyl-dGuo in DNA and lung tumor multiplicity are significantly decreased in animals treated with 4(R)-[4-2H1]NNK compared to those treated with unlabelled or 4(S)-[4-2H1]NNK (21). The initially formed intermediate shown here is converted to α-methylene-hydroxyNNK (7, Scheme 1) which spontaneously yields methanediazohydroxide and the methyl diazonium ion (shown). The latter reacts with DNA to produce the adduct O6-methyl-dGuo. Lung tumor multiplicity is highly correlated with levels of persistent O6-methyl-dGuo in DNA (22). This DNA adduct causes G → A mutations in codon 12 of the k-ras oncogene leading to lung tumor formation (23,24).