Page 373 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

340 SECTION | III Nanoparticles, Radiation and Carcinogens

VetBooks.ir TABLE 20.1 Some Examples of Chemical Carcinogens

Aflatoxin (from the fungus Aspergillus flavus)
Carcinogens occurring naturally
Aristolochic acid (in plant family Aristolochiaceae)
Toxic metals (e.g., As, Ni)
Safrole (from the root-bark or the fruit of sassafras plants)
Ionizing radiation
Carcinogens produced by industrial and Benzo[a]pyrene formed by incomplete combustion (e.g., vehicle emissions, tar and
nonindustrial processes asphalt fumes, meat barbeque)
Acrylamide formed during cooking French fries and potato chips
Tobacco smoke
Coal tar that is produced by the carbonization of coal, i.e., heating of coal in the
absence of air at very high temperatures
Benzene
Dyes (aromatic amines, such as 2-Naphthylamine)

such as inorganic, organic, fibers, plastic, hormones, etc. A genotoxic carcinogen can be a direct genotoxic car-
Table 20.1 shows some chemical carcinogens. cinogen or an indirect genotoxic carcinogen (procarcino-
gen). A direct genotoxic carcinogen is DNA-reactive
Chemical Carcinogens Can Be Genotoxic without metabolic activation, whereas an indirect geno-
or Nongenotoxic toxic carcinogen (procarcinogen) becomes DNA-reactive
following metabolic activation. Metabolic activation of
Based on their biological activities, chemical carcinogens
the indirect genotoxic carcinogen (procarcinogen) gener-
can be classified as genotoxic carcinogens that are DNA-
ates the ultimate carcinogen, which is DNA-reactive
reactive, and nongenotoxic carcinogens that are not DNA-
(Table 20.2). The majority of genotoxic carcinogens are
reactive.
indirect carcinogens because they need metabolic activa-
tion to form an electrophile that reacts with nucleophilic
Genotoxic (DNA-Reactive) Carcinogens Interact DNA (Marquardt, 1999).
With DNA
Most genotoxic carcinogens act as tumor initiators.
Genotoxic carcinogens interact directly with DNA through Nongenotoxic (Non DNA-Reactive) Carcinogens
the formation of covalent bonds, resulting in DNA- Do Not Directly Interact With DNA
carcinogen complexes (DNA adducts). These complexes Most nongenotoxic carcinogens act as tumor promoters
lead to various types of DNA damage, such as point muta- (Table 20.2). Nongenotoxic carcinogens do not directly
tions, chromosome breakage, fusion, missegregation and induce DNA damage. They can act through a number of
nondisjunction, all of which result in modifications to the different mechanisms, such as specific protein binding,
information stored in DNA as well as genomic instability. receptor interactions, hormonal and endocrine modifier
Some of the mechanisms underlying structural alterations effects, epigenetic changes in the DNA, etc. (Benigni
include the formation of cross-links between the two heli- et al., 2013). Thus, any genotoxic event in response to
ces, chemical bonds between adjacent bases, removal of challenge by nongenotoxic carcinogen is secondary to
DNA bases (hydration) and cleavage of the DNA strands. other biologic activity. For example, oxidative stress pro-
Such mutations are typically fixed by DNA repair mechan- duced by a nongenotoxic carcinogen as a primary effect
isms; however, if DNA replication occurs prior to the action can cause DNA damage as a secondary effect, but this
of a repair mechanism, mutations can become permanent secondary effect of DNA damage does not make the oxi-
(Lee et al., 2013). In addition, DNA repair process is not dative stress causing chemical a genotoxic carcinogen
devoid of errors; therefore, mutations can be induced by the (Trosko and Upham, 2005). Nongenotoxic carcinogens
very repair processes cells use to rid themselves of DNA usually exhibit tissue and species specificity.
damage. An affected cell first tries to reverse the damage Increasing evidence suggests that the demarcation
by DNA repair. If DNA repair and removal of the damage between genotoxic and nongenotoxic carcinogens may not
fails the cell often undergoes programmed cell death (apo- be as distinct as initially thought. For example, epigenetic
ptosis). If the cell fails to undergo apoptosis, the result is a changes may play a causative role in carcinogenic process
permanent fixation of the damage in the DNA, which pro- induced by genotoxic agents as well (Pogribny et al.,
vides the first trigger of tumor development. 2008). Tumor initiators can both initiate and promote