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Carcinogenesis: Mechanisms and Models Chapter | 20 341

VetBooks.ir TABLE 20.2 Examples of Genotoxic and Nongenotoxic Carcinogens

Type
Subtype and Mechanism of
Action Some Examples
Genotoxic carcinogen (DNA- Direct genotoxic carcinogen (No Nitrogen mustards (e.g., mechlorethamine, also known
reactive) Linear dose-response metabolic activation needed) as mustargen and mustine): Alkylate DNA
used for risk assessment Nitrosoureas (the simplest one is N-nitrosourea that has
Many compounds in this class are an H-atom for the R 1 ,R 2 and R 3 groups. The H can be
used as chemotherapeutic agents substituted to give rise to more complex nitrosoureas,
0
because they are cytotoxic such as N-methyl-N-nitrosourea or MNU; N,N ‑bis
(2‑chloroethyl) nitrosourea or BCNU): Alkylate DNA
β-propiolactone: Alkylates DNA (used as antiviral)
Indirect genotoxic carcinogen Polycyclic aromatic hydrocarbons, such as benzo[a]
(metabolic activation needed) pyrene (B[a]P-7,8-dihydrodiol-9,10-epoxide is the
ultimate carcinogen produced from the metabolism of
The carcinogenic metabolite is benzo[a]pyrene)
called the ultimate carcinogen Aromatic amines (The key reaction producing the
ultimate carcinogen is the N-oxidation to aryl-N-
hydroxylamines that form esters. An example is
N-acetoxyarylamine produced from 2-naphthylamine. In
acidic pH, such as in urine these metabolites produce
aryl nitrenium ion which is DNA-reactive; hence
aromatic amines often induce bladder tumor)
Aflatoxin B1 (AFB 1 -exo-8,9-epoxide is the ultimate
carcinogen produced from the metabolism of aflatoxin
B1)
Nongenotoxic carcinogen (non Protein binding D-limonene (binds α 2u G in the kidney of male rats; α 2u G
DNA-reactive) Nonlinear dose- is not degraded, hence accumulates in the proximal
response possible tubular cells, becomes cytotoxic and causes cell death by
necrosis. A sustained compensatory cell proliferation
results in malignancy)
Receptor activation PCBs, Dioxins: AhR activation (causes dysregulation of
cellular physiology, growth and proliferation)
Fibrates, such as Clofibrate, Ciprofibrate: PPARα
activation (induces oxidative stress and DNA damage as
a2 effect of oxidative stress; alters hepatocyte growth

control)
Endocrine modifier Diethylstilbesterol and other phytoestrogens
DNA methylation (epigenetic) Wy-14643, Trichloroethylene (can also cause
peroxisome proliferation) (cause promoter
hypomethylation of oncogenes, such as c-Jun, c-Myc,
and dysregulation of cell proliferation)

tumor development and also cause progression to nongenotoxic carcinogens (tumor promoters) is an impor-
malignancy, if applied repetitively (Tennant, 1999). There tant aspect of the study of chemical carcinogenesis.
are relatively few DNA reactive complete carcinogens
that can induce cancers following single exposures (e.g.,
X-rays, urethane, and ethyl nitrosourea). For most other Carcinogens and Dose-Response
carcinogens, repetitive or prolonged exposures are neces- In cancer risk assessment, the dose-response to genotoxic
sary. Additionally, new chemicals introduced into carcinogens is assumed to be linear, i.e., a straight line
commerce or the environment are rarely traditional approaching zero. In other words, there is no safe level of
genotoxic carcinogens (Tennant, 1999). Thus, the study of exposure; any exposure to a genotoxic carcinogen is