Understanding Genotoxic Carcinogens

This assignment delves into the complexities of genotoxic carcinogens. It examines how these agents contribute to cancer development by altering DNA sequences. The text focuses on the distinction between proto-oncogenes and tumor suppressor genes (TSGs), explaining how their mutations can lead to uncontrolled cell growth and cancer. The role of chromosomal translocations, enhancer insertions, point mutations, and gene amplification in oncogene activation is also discussed.

Running head: GENERAL TOXICOLOGY ASSIGNMENT 13
General toxicology assignment 13
Name of the Student
Name of the University
Author note

1GENERAL TOXICOLOGY ASSIGNMENT 13
Genotoxic carcinogens are divided into categories: direct and indirect carcinogens that
initiate tumours through the production of DNA damage.
A primary or direct acting carcinogen is a chemical that do not require any kind of
chemical modification or metabolic activation for inducing cancer called activation- independent
carcinogens being highly reactive electrophilic molecules act by binding to cellular
macromolecules, DNA (Klaunig, 2014). On the other hand, indirect-acting genotoxic
carcinogens require metabolic activation from proximate carcinogen or procarcinogen to
carcinogen like Nicotine-derived nitrosamine ketone (NNK), benzo[a]pyrene and alfatoxin B1.
Direct carcinogens like dimethylcarbamyl chloride and Dimethyl sulphate does not require any
chemical transformation for the carcinogenicity production. On a contrary, procarcinogens or
indirect acting compounds as polycyclic aromatic hydrocarbons require the metabolic conversion
for the final production of carcinogen that has the capability of carcinogenicity or induce
tumours (Stanley, 1995).
Direct acting carcinogens like alkylating and acylating agents does not uncoil or coil
DNA properly or information-decoding enzymes do not process it. As a result, there is
cytotoxicity and inhibition of cell growth and initiation of apoptosis or programmed cell death.
Direct carcinogens that increase the incidence of cancer after chemical exposure also trigger
mutations (Smith et al., 2016).
Indirect carcinogens or pro-carcinogens are changed in the body after exposure into
carcinogens that cause cancer at other sites except for the exposure site. They are activation
dependent and require cellular enzymatic metabolism that exert action just as direct acting
carcinogen. In general, metabolism is the attempt made by body to detoxify exogenous

2GENERAL TOXICOLOGY ASSIGNMENT 13
chemicals conjugation with water solutes that can be excreted. However, body exposure to
chemical and detoxification results in activation of that chemical into ultimate carcinogen that
can induce cancers (Oliveira, 2016).
Epigenetic carcinogen does not damage the DNA on its own, however, make alterations
in the body predispose to cancer. It is different from genotoxic carcinogens as they directly react
with DNA or any macromolecule inducing cancer. They are non-genotoxic chemical carcinogens
that function to induce tumour formation by modulating the cell growth, inducing cell death or
by exhibiting dose dependent relationships between exposure of chemical and tumour formation.
Chemicals like arsenite, diethylstilbestrol, nickel compounds and hexachlorobenzene increases
the incident of tumours, however, does not show any mutagen activity like pathogens or toxic
compounds. The epigenetic carcinogens cause modification of gene expression, functional
developmental changes or exogenous factors that induce cancer. DNA hypemethylation causes
down-regulation of tumour suppressor genes (TSG) and hypomethylation results in up-regulation
of oncogenes in epigenetic mechanism of carcinogenesis where it does not change the basic
structure and sequence of DNA. The growth factors, hormones interact with their receptors for
production and different differentiation processes and other processes like inflammation,
restorative growth and cytotoxicity. Due to the action of epigenetic carcinogens, there is gene
repression, activation or derepression, stimulation of cell division and clonal expansion that
alters the cell and as a result, cell communication is disrupted. These mechanisms induce normal
cell to induce mutation and the initiated cell becomes transformed cell in the promotion stage.
After progression, there is survival advantage of the malignant sub-populations resulting in
cancer cells and carcinogenesis (Herceg et al., 2013).

3GENERAL TOXICOLOGY ASSIGNMENT 13
Proto-oncogenes are normal genes that help in cell growth normally, however, when it
undergoes mutations or changes to become activated uncontrollably becoming oncogene. When
mutations occur in DNA sequence, it gives rise to oncogene that interferes with normal cell
division regulation. The proto-oncogene activation is achieved by mechanisms like chromosomal
translocation, enhancer and promoter insertion, point mutations or gene amplification. Mutation
in one allele is enough to cause oncogenic activity and often acting as dominant to wild type.
There is “gain of function” of the protein signalling uncontrolled cell division and conversion
occurs from proto-oncogene to oncogene. There is some tissue preference in this mechanism.
Mutation occurs in somatic cells and therefore, it is not inherited (Hnisz et al., 2016).
On the other hand, TSGs are found normally on a cell surface and its function is the
regulation of cell division by slowing of division process, coupling to DNA damage in cell cycle,
cell repair mechanism or the induction of apoptosis. It is different from proto-oncogene as
oncogene is formed due to activation of proto-oncogene whereas TSG cause cancer in activated
form. Only one allele of TSG that is mutated is not enough to cause cancer rather two mutant
form of TSG alleles are required to cause cancer as one normal allele has the signal for stopping
cell division. Examples, p53 protein and Rb gene are TSGs and “loss of function” mechanism of
protein results in malfunctioning of TSGs. There is strong tissue preference in TSGs, for
example, the Rb II gene in retina blastoma (Harris, 1996).

4GENERAL TOXICOLOGY ASSIGNMENT 13
References
Harris, C. C. (1996). p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis,
molecular epidemiology, and cancer risk assessment. Environmental health
perspectives, 104(Suppl 3), 435.
Herceg, Z., Lambert, M. P., van Veldhoven, K., Demetriou, C., Vineis, P., Smith, M. T., ... &
Wild, C. P. (2013). Towards incorporating epigenetic mechanisms into carcinogen
identification and evaluation. Carcinogenesis, 34(9), 1955-1967.
Hnisz, D., Weintraub, A. S., Day, D. S., Valton, A. L., Bak, R. O., Li, C. H., ... & Reddy, J.
(2016). Activation of proto-oncogenes by disruption of chromosome
neighborhoods. Science, aad9024.
Klaunig, J. E. (2014). Chemical carcinogenesis. Principles of Toxicology: Environmental and
Industrial Applications 2014, 259.
Oliveira, P. A. (2016). Chemical carcinogens. Oxford Textbook of Oncology, 142.
Smith, M. T., Guyton, K. Z., Gibbons, C. F., Fritz, J. M., Portier, C. J., Rusyn, I., ... & Hecht, S.
S. (2016). Key characteristics of carcinogens as a basis for organizing data on
mechanisms of carcinogenesis. Environmental health perspectives, 124(6), 713.
Stanley, L. A. (1995). Molecular aspects of chemical carcinogenesis: the roles of oncogenes and
tumour suppressor genes. Toxicology, 96(3), 173-194.