Page 377 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

344 SECTION | III Nanoparticles, Radiation and Carcinogens

VetBooks.ir the mutations that outnumber the driver mutations do not compound needs to be metabolized into a carcinogenic
metabolite, which is called the ultimate carcinogen. The
confer any survival advantage to the cells and do not con-
carcinogens form DNA adducts that are often, but not
tribute to the overall process of carcinogenesis; these neu-
tral mutations are called passenger mutations. Table 20.4 always, properly repaired. The biological activity of the
lists some common tumor progression agents with no carcinogens depends on a balance between their activation
initiator activity. and detoxification in the target tissue.

Carcinogenesis as a Function of Age and The Majority of Genotoxic Carcinogens Interact
the Multistage Model of Carcinogenesis With DNA Through Three Different Types of
Chemical Reactions: Alkylation, Arylamination, and
The initiation-promotion-progression model of carcinogen- Aralkylation
esis discussed above is about the biological mechanism of
carcinogenesis. The multistage model of carcinogenesis The DNA-reactive groups are generated through spe-
(Armitage and Doll, 1954) is a mathematical model that cific reaction chemistries, such as oxidation at carbon-
integrates data from the initiation-promotion experiments carbon double bonds yielding alkylating or aralkylating
as well as epidemiological data to provide a power law to agents; oxidation or reduction at nitrogen producing
the age incidence of cancer. arylaminating agents; conjugations of hydroxy com-
pounds producing aralkylating or arylaminating agents
In their original paper, Armitage and Doll (1954)
and conjugation between glutathione with dihaloalkanes
showed that when the cancer incidence rate (as measured
producing alkylating agents. There are some carcino-
by cancer-associated mortality rate) and age were plotted
gens that do not fit these categories, such as acylating
on a logarithmic plot, the relationship was linear with a
agents, α,β-unsaturated aldehydes, chloroethylene
slope of about six. In other words, with each unit increase
oxide, etc. (Dipple, 1995).
in the logarithm of age, there was a six-unit increase in
the logarithm of cancer incidence rate, as measured by
cancer-associated mortality rate. Alkylation Involves the Addition of an Alkyl
Based on their findings, Armitage and Doll (1954) Carbocation to DNA
proposed what is commonly known as the multistage Alkylating carcinogenic agents add an electrophilic (elec-
model of carcinogenesis. They inferred that six or tron-poor) alkyl carbocation to nucleophilic (electron-rich)
seven independent, sequential, and stable events are sites in DNA. Carbocations, formerly known as carbonium
needed to occur in the cancer lineage before malig- ions, carry a positive charge on a carbon atom. The reactiv-
nancy could be observed. Therefore, according to this ity of alkyl carbocations from higher to lower is as follows:
model, cancer is the end-result of a series of discrete methyl carbocation (also known as methyl carbonium ion;
1
1
cellular changes with a long latency period before CH 3 ) . primary alkyl carbocation (R 1 CH 2 ;R 1 5 single
1
cancer is manifest. Armitage and Doll’s original model alkyl group) . secondary alkyl carbocation (R 2 CH ;
has been subsequently refined by many authors. The R 2 5 two alkyl groups) . tertiary alkyl carbocation
1
multistage model does not hold particularly true for (R 3 C ;R 3 5 three alkyl groups). Examples of alkylating
hormonal carcinogenesis, nor for cancers in people agents include nitrosamines, aliphatic epoxides, aflatoxins,
above the age of 75 because at this age cancer inci- lactones, nitrosoureas, nitrogen mustards, haloalkanes, aryl
dence significantly drops. triazenes, and sultones (Dipple, 1995). The sites of substi-
Before Armitage and Doll proposed their multistage tution in DNA bases by alkylating agents are many (see
Figure 26.2 in Choudhuri et al., 2012). Alkylating agents
model of carcinogenesis, Nordling (1953) hypothesized
are produced by enzymatic reactions, such as P450-
that cancer development requires mutations in multiple
mediated microsomal oxidation in the liver.
genes. As mentioned above, Knudson’s two-hit hypothesis
An example of alkyl carbocation alkylating agent is
is the simplest form of this multiple hit hypothesis. Based
1
methyl carbonium ion (CH 3 ) produced by P450 2E1
on the current state of understanding of carcinogenesis,
(CYP2E1)-mediated metabolism of dimethylnitrosamine.
the inferred six or seven independent events that
Armitage and Doll hypothesized as needed for cancer Methyl carbonium ion is a highly reactive alkylating
development, may be all genetic events or a combination agent that methylates DNA and proteins (Fig. 20.2A).
of genetic and epigenetic events. Another example is the aflatoxin B1 (AFB 1 )-exo-8,9-
epoxide produced by the metabolism of AFB 1 .The
AFB1-exo-8,9-epoxide forms DNA adducts almost
Mode of Action of Chemical Carcinogens exclusively at the N-7 position of guanine (Fig. 20.2B)
As discussed above, the majority of genotoxic carcinogens that ultimately results in a GC-TA transversion. These
are indirect genotoxic carcinogens because the parent mutations are thought to be the major mechanism of