DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 67–1
Examples of Important Carcinogens a
CARCINOGEN CLASS EXAMPLE SOURCE MECHANISM
Genotoxic
Nitrosamines Nicotine-derived Tobacco products Metabolic activation to form DNA adducts
nitrosaminoketone
(NNK)
Polycyclic aromatic Benzo[a]pyrene Fossil fuel combustion, Metabolic activation to form DNA adducts
hydrocarbons tobacco smoke, charbroiled or ROS
food
Aromatic amines 2-Aminonaphthalene Dyes Metabolic activation to form DNA adducts
Fungal toxins Aflatoxin B 1
Corn, peanuts, and other food Metabolic activation to form DNA adducts
Non-genotoxic
Liver toxicants Ethanol Beverages, environment Toxicity and compensatory proliferation;
depletion of GSH
Phorbol esters Tetradecanoyl Horticulture; rubber and Activation of PKC isoforms
phorbol acetate gasoline production
Estrogens Diethylstilbestrol Drugs, environment Activation of estrogen-receptor signaling
Metals Arsenic Environment, occupation Inhibition of DNA repair; activation of signal
transduction pathways
Irritants Asbestos Environment, occupation Stimulation of inflammation; formation of ROS
Dioxins TCDD Waste incineration, herbicides, Activation of the aryl hydrocarbon receptor
paper-pulp bleaching
a
Compounds in this table are classified as group 1 carcinogens by the International Agency for Research on Cancer (IARC), with the exception of
the phorbol esters, which have not been examined. TCDD, 2,3,7,8 tetrachlorodibenzo-p-dioxin; ROS, reactive oxygen species; GSH, glutathione;
PKC, protein kinase C.
group 2A includes chemicals that probably are carcinogenic
in humans; group 2B chemicals possibly are carcinogenic
in humans; group 3 chemicals lack data to
suggest a role in carcinogenesis; and group 4 are those
with data indicating they are unlikely to be carcinogens.
Some important group 1 carcinogens and their sources
are given in Table 67–1.
The transformation of a normal cell to a malignancy
is a multi-stage process, and exogenous chemicals can act
at one or more of these stages (Figure 67–2). A classic
model of chemical carcinogenesis is tumor initiation
followed by tumor promotion. In this model, a tumor initiator
causes gene mutations that increase the ability of
cells to proliferate and avoid apoptosis. A tumor promoter
does not directly modify genes but changes signaling
pathways and/or the extracellular environment to cause
initiated cells to proliferate, invade surrounding tissue,
and increase access to blood vessels. Although this model
is an oversimplification of the many processes of carcinogenesis,
it demonstrates the types of changes that must
occur to transit a normal cell into tumorigenesis.
Chemical carcinogens cause cancer through genotoxic
and non-genotoxic mechanisms (Figure 67–2).
Genotoxic carcinogens induce tumor formation through
damage to DNA. Typically, genotoxic carcinogens
undergo metabolism in a target tissue to a reactive intermediate.
This reactive intermediate can directly damage
DNA via covalent reaction to form a DNA adduct.
Alternatively, it can indirectly damage DNA through
the formation of reactive oxygen species (ROS), which
can oxidize DNA or form lipid peroxidation products
that react with DNA (Mena et al., 2009).
Benzo[a]pyrene, a key carcinogen in tobacco smoke, is an
example of a genotoxic carcinogen that forms both direct DNA
adducts and ROS. Benzo[a]pyrene is oxidized by CYPs to a 7,8-dihydrodiol,
which represents a proximate carcinogen (a more carcinogenic
metabolite). This metabolite can either undergo a second
oxidation step by a CYP to form a diol epoxide, which readily reacts
with DNA, or it can undergo oxidation by aldo-keto reductases to
form a catechol, which will redox cycle to form ROS (Conney, 1982;
Penning, 2009).
If DNA damage from a genotoxic carcinogen is not repaired
prior to DNA replication, a mutation can result. If this mutation is in
a key tumor suppressor gene or proto-oncogene, it provides advantages
in proliferation or survival. Alternatively, if the mutation is in
a DNA repair gene, the mutation increases the probability that other
mutations will occur. Given mutations in enough key genes and the