Tobacco and Public Health - TCSC Indonesia

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TOBACCO SMOKE CARCINOGENS: HUMAN UPTAKE AND DNA INTERACTIONS
NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
(NNAL) are the only known pancreatic carcinogens in cigarette smoke (Rivenson et al.
1988). Low doses of these N-nitrosamines induce pancreatic tumors in rats, in addition
to lung tumors (Hecht 1998). Pancreatic tumors are also observed in the offspring of
pregnant rats treated with NNK, and this effect is markedly enhanced by ethanol
(Schüller et al. 1993).
4-Aminobiphenyl and 2-naphthylamine are known human bladder carcinogens
(International Agency for Research on Cancer 1972b, 1974b). Both are present in cigarette
smoke. Hemoglobin adducts of 4-aminobiphenyl and other aromatic amines
have been used as dosimeters of 4-aminobiphenyl uptake in humans, and their levels
are associated with bladder cancer induction in smokers (Castelao et al. 2001). The
evidence is strong that aromatic amines play a significant role as causes of bladder
cancer in smokers (Vineis et al. 2001).
Cigarette smoke contains free radicals and induces oxidative damage (Pryor 1997;
Arora et al. 2001). The gas phase of freshly generated cigarette smoke has large
amounts of nitric oxide and other unstable oxidants (Hecht 1999). The particulate
phase is postulated to contain long-lived radicals that may undergo quinone–
hydroquinone redox cycling (Pryor 1997). The presence of such free radicals and
oxidants can lead to oxidative DNA damage. However, the role of oxidative damage in
cancer induced by cigarette smoke is unclear.
Urinary metabolites as biomarkers of tobacco
carcinogen uptake in humans
It is important to understand the carcinogen dose in smokers. Carcinogen-related
biomarkers, such as metabolites or adducts, have been used to quantify carcinogen
uptake in humans. DNA adduct measurements give direct information on the extent of
carcinogen reactions with DNA (Bartsch 1996; Phillips 1996; Poirier and Weston 1996;
Kriek et al. 1998). If measured in target tissues or cells, DNA adduct levels could relate
directly to risk, because DNA adducts are central to the carcinogenic process. There are
technical problems associated with the measurement of specific DNA adducts, but
nevertheless some valuable information is available. Tobacco carcinogen-DNA adducts
are discussed later in this chapter. Protein adducts have frequently been used as surrogates
for DNA adducts because the two parameters tend to be correlated, and protein,
such as hemoglobin or albumin, is relatively easy to obtain in large quantities
(Ehrenberg and Osterman-Golkar 1976; Skipper and Tannenbaum 1990). There are no
known repair processes for protein adducts and they accumulate over the lifetime of
the protein in which they are formed, potentially providing an integrated measure of
exposure. A third type of carcinogen biomarker is urinary metabolites, which will be
the focus of human tobacco carcinogen uptake studies discussed here. Urinary
metabolites have certain advantages. Important among these is their quantity, which is