Tobacco and Public Health - TCSC Indonesia

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TOBACCO SMOKE CARCINOGENS: HUMAN UPTAKE AND DNA INTERACTIONS
smokers, and in 12 per cent of those from nonsmokers, a significant difference.
G→A mutations in p53 occur in 29 per cent of lung cancers from smokers and in
47 per cent of those from nonsmokers. Other studies show a positive relationship
between lifetime cigarette consumption and the frequency of p53 mutations and G→T
mutations on the nontranscribed (slowly repaired) DNA strand. These observations
are generally consistent with the fact that most activated carcinogens react predominantly
at G in DNA, as outlined in Table 5.3 and that many of the adducts so formed
cause G→T or G→A mutations. It has been hypothesized that G→T mutations, in
particular, are characteristic of lung cancer and result from interactions of the p53 gene
with metabolically activated cigarette smoke carcinogens (Pfeifer et al. 2002).
Mutations in the p53 gene in lung cancer frequently occur at codons 157, 158, 245,
248, and 273, and are commonly G→T mutations (Pfeifer et al. 2002). These mutations
have been called ‘lung cancer hotspots’. Reactions of PAH diol epoxide metabolites
with the p53 gene in vitro result in frequent adduct formation at codons 156, 157,
158, 245, 248, and 273, leading to the hypothesis that PAHs such as BaP are the responsible
agents in cigarette smoke for the observed mutations. Apparently there is
enhanced adduct formation when a 5-methyldeoxycytidine nucleotide is adjacent to
the modified deoxyguanosine (CpG dinucleotide sequence). In the p53 gene of lung
cancer, five major G→T mutation sites (codons 157, 158, 245, 248, and 273) have
methylated CpG sequences. However, it should be noted that a number of different
activated carcinogens, such as those summarized in Table 5.3, can react at these
positions. Because of the complexity of DNA adduct formation by cigarette smoke
carcinogens, it is unlikely that the observed mutations result from reactions only with
metabolically activated PAH. Nevertheless, in aggregate, the common occurrence of
G mutations in lung cancer is consistent with the higher reactivity of G than other
DNA bases with metabolically activated carcinogens.
Mutations in codon 12 of the K-ras oncogene are found in 24–50 per cent of human
adenocarcinoma of the lung (Hecht 1999). They are more common in smokers than in
nonsmokers. The most common mutation is from the normal GGT sequence to TGT, a
G→T mutation. This accounts for about 60 per cent of the observed mutations in
codon 12. GGT→GAT mutations are observed in 20 per cent and GGT→GTT mutations
in 15 per cent. This pattern is quite similar to that observed in lung tumors from
mice treated with PAHs. Other tobacco smoke carcinogens may also produce this
pattern of mutations.
Summary
There is a wealth of data generally consistent with the mechanistic framework presented
in Fig. 5.1. Over 60 carcinogens have been identified in cigarette smoke, and their
abilities to induce tumors at specific sites associated with tobacco-induced cancer in
humans are, in many cases, well established. There is convincing evidence that smokers
and people exposed to ETS take up and metabolize these carcinogens. In some cases,