world cancer report - iarc

of the effective biological exposure, and
hence of carcinogenic risk in humans [5].
However, analysis of DNA adducts in
human cells and tissues remains difficult,
due to the very low levels of adducts
present in DNA (typically, one adduct per
10 7-10 8 parent nucleotides).
Activities of the enzymes involved in carcinogen
metabolism vary greatly between
individuals due to induction and inhibition
processes or to gene polymorphisms that
can affect activity. These variations can
affect the formation of carcinogen-DNA
90 Mechanisms of tumour development
adducts, together with other genetic
determinants that regulate DNA repair or
cell cycle control, for example, and thus
affect the outcome of exposure to DNAdamaging
agents and influence cancer
risk in different individuals [6]. Many studies
have sought to correlate genetic polymorphisms,
adduct levels and cancer risk
in human populations (Genetic susceptibility,
p71). These studies have hitherto
provided some correlations for risk prediction
at the population level. However,
due to the great number of enzymes and
polymorphisms involved, large-scale studies
and high throughput assays (based on
DNA microchips, for example) will be
required to fully elucidate the complex
nature of such gene-environment interactions.
Mutational spectra
Adducts of DNA and proteins can be used
as early markers of exposure to carcinogens
as indicated. However, because
adducts only persist for a short time (typically,
for a few hours or days for DNA
Fig. 3.8 Carcinogen activation by mammalian enzymes: reactions catalysed during metabolism of benzo[a]pyrene and NNK (4-(methylnitrosamino)-1-(3pyridyl)-1-butanone),
both contained in tobacco, and of aflatoxin B 1, produce reactive intermediates (ultimate carcinogens, in box), which bind to DNA. Other
reaction pathways leading to the formation of glucuronides and other esters, which are excreted, are not shown. 1. Benzo{a}pyrene-7, 8-diol-9, 10-epoxide; 2. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol;
3. Diazohydroxide; 4. Diazohydroxide; 5. Aflatoxin B 1 -8,9-oxide; 6. 2,3-Dihydro-2-(N 7- guanyl)-3-hydroxyaflatoxin B 1 .