Tobacco and Public Health - TCSC Indonesia

(Kozack et al. 2000; Seo et al. 2000). Some PAH diol epoxides, such as those derived
from benzo[c]phenanthrene, react extensively at deoxyadenosine in DNA and consequently
produce significant levels of A mutations (Bigger et al. 1992; Szeliga and
Dipple 1998).
7-Alkyldeoxyguanosines, such as those derived from N-nitrosodimethylamine,
NNK, ethylene oxide, 1,3-butadiene, and vinyl chloride, readily depurinate, giving rise
to abasic sites. Replication past abasic sites results predominantly in GC→TA mutations
(Kunkel 1984). Therefore, these cigarette smoke constituents can be expected to
produce GC→TA mutations in pulmonary DNA. Pyridyloxobutylation of DNA gives
both GC→TA and GC→AT mutations, as demonstrated by analysis of ras mutations
in lung DNA of mice treated with a model pyridyloxobutylating compound, NNKOAc
(Ronai et al. 1993).
Site-specific mutagenesis experiments in human embryonic kidney cells have shown
that the mispairing characteristics of O 6 -pyridyloxobutyldeoxyguanosine are comparable
to those of O 6 -methyldeoxyguanosine, with a high number of G→A transitions
and smaller amounts of G→T transversions and other mutations observed (Pauly et al.
2002).
GC→TA mutations are also the predominant ones observed in studies of mutagenesis
by N 2 -deoxyguanosine adducts of 1,3-butadiene (Carmical et al. 2000), adducts of
4-aminobiphenyl (Melchior et al. 1994), and 8-oxodeoxyguanosine (Moriya 1993).
Other studies of butadiene mutagenesis demonstrate the occurrence of GC→AT,
AT→TA, and GC→TA mutations (Recio et al. 2000). Products of the further oxidation
of 8-oxodeoxyguanosine by peroxynitrite are highly efficient in producing GC→TA
mutations (Henderson et al. 2002).
Collectively, the available data indicate that many DNA adducts associated with
cigarette smoke exposure produce GC→TA mutations. A number of other types of
mutations are also produced. It is easy to see how tobacco carcinogens can produce
multiple mutations in smokers’ DNA.
Effects of tobacco smoke carcinogens on the p53 and
K-ras genes
STEPHEN S. HECHT 113
The preceding sections provide definitive evidence that tobacco smoke carcinogens are
taken up by smokers and metabolically activated to forms that react with DNA. The
resulting DNA adducts can cause mutations. If these mutations occur in critical genes
such as the p53 tumor suppressor gene and the K-ras oncogene, cancer can result
because the normal role of these genes in the delicate growth control processes of the
cell is subverted. Extensive studies have examined mutations in the p53 gene in lung
tumors (Hecht 1999; Pfeifer et al. 2002). Mutations in the p53 gene are found in
approximately 40 per cent of human lung cancers and are more common in smokers
than in nonsmokers. G→T mutations in p53 occur in 30 per cent of lung cancers from