Progress and challenges in selected areas of tobacco carcinogenesis

Abstract

Tobacco use continues to be a major cause of cancer in the developed world, and despite significant progress in this country in tobacco control, which is driving a decrease in cancer mortality, there are still over 1 billion smokers in the world. This perspective discusses some selected issues in tobacco carcinogenesis focusing on progress during the 20 years of publication of Chemical Research in Toxicology. The topics covered include metabolism and DNA modification by tobacco-specific nitrosamines, tobacco carcinogen biomarkers, an unidentified DNA ethylating agent in cigarette smoke, mutations in the K-RAS and p53 gene in tobacco-induced lung cancer and their possible relationship to specific carcinogens, secondhand smoke and lung cancer, emerging issues in smokeless tobacco use, and a conceptual model for understanding tobacco carcinogenesis. It is hoped that a better understanding of mechanisms of tobacco-induced cancer will lead to new and useful approaches for the prevention of lung cancer and other cancers caused by tobacco use.

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).

Figure 2

Total POB-DNA adduct levels in the lungs of rats treated with NNK (closed diamonds), (S)-NNAL (open squares) or (R)-NNAL (closed squares). Rats were treated with 10 ppm of each compound added to their drinking water and were killed at the time intervals shown. Individual POB-DNA adducts were analyzed by LC-ESI-MS/MS-SRM as described (28).

Figure 3

Current model for the selective induction of induce lung tumors in rats treated with NNK. Upon administration to rats, NNK is enzymatically reduced to NNAL, with (S)-NNAL predominating (34). (S)-NNAL is hypothesized to bind to an as yet uncharacterized pulmonary receptor causing its accumulation and persistence in the lung (29). It is presumed to be slowly released from this receptor site and enzymatically reconverted to NNK, at least in part by P450s (20). This NNK then undergoes metabolic activation by P450 2A3 and other P450s in the lung, resulting in POB-DNA adducts (shown) and Me-DNA adducts (see also Scheme 1) (8,20). The persistence of these adducts in Type II cells and Clara cells of the rat lung is believed to result in mutations and lung tumor induction.

Figure 4

A. Median serum cotinine levels in non-smokers, by age group, 1988–2002, according to data from the Centers for Disease Control and Prevention NHANES study, (137). B. Sustained decline of smoking prevalence in the United States, from 1983–2003 (138).

Figure 5

Conceptual model for understanding mechanisms of tobacco carcinogenesis. The central track involving carcinogen-DNA adduct formation and consequent mutations in critical genes is the major accepted pathway. The top and bottom tracks also contribute but their roles are less well defined. Molecular pathways involved in the box labeled “Loss of Normal Growth Control Mechanisms” have been described by Weinberg (139).

Scheme 1

DNA adduct formation from NNK, NNN, and NNAL.

Scheme 2

Metabolism of phenanthrene (30) to a bay region diol epoxide (33) and PheT (34).