A Review on Genotoxicity
Ahamed Noor Mansoori, Rupesh K. Gautam*, Prafulla C. Tiwari
Department of Pharmacology, Jaipur College of Pharmacy, ISI-15, RIICO Institutional
Area, Tonk Road, Sitapura, Jaipur, India-302022
ABSTRACT:
Genotoxicity studies used to
investigate the potency of a compound to interact with the constitution of
genetic. An alteration of the genetic code via gene mutations (point mutations)
or DNA strand breaks may lead to fundamental changes DNA damage in a somatic cell may result in
a somatic mutation, which may lead to malignant transformation (cancer). A genotoxin is an agent or chemical that can cause DNA or
chromosomal damage. Such damage in a germ cell has the potential to cause a
heritable altered trait (germline mutation). Many
chemical carcinogens/ mutagens undergo metabolic activation to reactive species
that bind covalently to DNA, and the DNA adducts thus formed can be detected in
cells and in human tissues by a variety of sensitive techniques. The present
study was aimed to provide information regarding genotoxicity.
KEY
WORDS: Genotoxin,
Chromosomal damage, Carcinogen, Gene mutations.
INTRODUCTION:
Genotoxicity is an important word in genetics defined
as a destructive effect on a cell's genetic material (RNA, DNA) affecting its
integrity. Genotoxins are mutagens; they can cause
mutations. Genotoxins include both chemical and
radiation genotoxins. A substance that has the
property of genotoxicity is known as a genotoxin. 1
Genotoxicity describes the property of chemical agents that destroy the
genetic information within a cell causing mutations,
which may lead to cancer. While genotoxicity is often
confused with mutagenicity, it is important to know
that all mutagens are genotoxic; however, not all genotoxic substances are mutagenic. 2
Genotoxin: A genotoxins is a chemical or agent that
can cause chromosomal or DNA damage. Such damage in a germ cell has the
potential to cause a heritable altered trait (germ line mutation). DNA damage
in a somatic cell may result in a somatic mutation, which may lead to malignant
transformation (cancer). Many in-vitro
and in-vivo tests for genotoxicity have been developed that, with a range of
endpoints, detect DNA damage or its biological consequences in prokaryotic
(e.g. bacterial) or eukaryotic (e.g. mammalian, yeast or avian) cells.
The detection and characterization of DNA adducts in human tissues
gives clues to the etiology of human cancer. Characterizations of gene
mutations in human tumor’s, in common with the known mutagenic profiles of genotoxins in experimental systems, may provide further
insight into the role of environmental mutagens in human cancer. 3
Agents capable of causing
direct or indirect damage to DNA:
· Electrophilic species forming covalent adducts to DNA
e.g. Alkylating agents –Aryl
nitrenium ions, Diol epoxides of PAH etc.
· Nucleoside analogues
· UV and ionizing radiations
· Topoisomerase inhibitors
· Reactive oxygen species
· Protein synthesis inhibitors 1
· Herbal Plants like Aconite, Alfa alfa, Calamus, Borage, Chaparrel, Colts
foot, Comfrey, Germander, Ephedra, Senna, Ginkgo biloba,
Ginseng, Glycyrrhiza glabra
(Liquorice), Isabghol, Aloe
vera, Sassafras, Silybum
marianum 4.
Figure 1: The
inter-relationships of genotoxicity and
carcinogenicity
Herman Druckrey, at a conference in Sweden, first used the word genotoxic for chemicals that can react with DNA, and thus
have the potential of being mutagenic, carcinogenic and cell transforming. It
has been popularized the use of the term genotoxic as
agents that were DNA-reactive, directly or after biochemical activation, with
appropriate fractions from liver or other tissue of rodents or humans. In sharp
contrast, there are other chemicals and agents that are clearly not mutagenic,
but that have the ability of increasing the efficiency or effectiveness of a genotoxic carcinogen. The classic promoters of
carcinogenesis fall into that class, but there are other non genotoxic agents such as immunological elements, endocrine
factors and related properties that are of demonstrated relevance in the
complex overall carcinogenic process, as we now understand. One key property of
this class of agents is that they may control the rate of DNA synthesis and of
cell division. This is important ever since Cleaver discovered repair of DNA. A
cell containing mutated DNA yield an abnormal fraudulent DNA only after such a
DNA has served as a template in the synthesis of new DNA during mitosis and
cell cycling. Thus, the rate of cell division is an important parameter.
Nevertheless, simple screening bioassays can play very important role in
pre-regulatory genotoxicity screening strategies
because of their rapid genotoxicity detection
requirement that is demanded in preliminary decision making process. 5
The
alteration can have direct or indirect effects on the DNA:
The
induction of mutations, mistimed event activation, and direct DNA damage
leading to mutations.
The permanent, hereditary changes can affect either somatic cells of
the organism or germ cells to be passed on to future
generations. Cells prevent expression of the genotoxic
mutation by either DNA repair or apoptosis; however, the damage
may not always be fixed leading to mutagenesis.
Mechanisms:
The genotoxic substances induce damage to the genetic material
in the cells through interactions with the DNA structure and sequence. For
example, the transition metal chromium interacts with DNA in its
high-valent oxidation state so to occur DNA lesions
leading to carcinogenesis. The metastable oxidation
state Cr (V) is achieved through reductive activation. The researchers
performed an experiment to study the interaction between DNA with the
carcinogenic chromium by using a Cr (V)-Salen complex
at the specific state of oxidation. The interaction was specific to
the guanine nucleotide in the genetic sequence.
Figure: 2
Definition of transitions and transversions, they are
a common mutation caused by genotoxic compounds
In order to narrow the interaction between the Cr (V)-Salen complex with the guanine base, the researchers modified the bases to 8-oxo-G so to have site specific oxidation. The reaction between the two molecules caused DNA lesions; the two lesions observed at the modified base site were spiroiminodihydantoin and guanidinohydantoin. To further analysis of the site of lesion, it was observed that polymerase stopped at the site and adenine was inappropriately incorporated into the DNA sequence opposite of the 8-oxo-G base. Therefore, these lesions predominately have G >T transversions. High-valent chromium is seen to act as a carcinogen as researchers found that "the mechanism of damage and base oxidation products for the interaction between DNA and high-valent chromium are relevant to in-vivo formation of DNA damage leading to cancer in chromate-exposed human populations." Consequently, it shows how high-valent chromium can act as a carcinogen with 8-oxo-G forming xenobiotics
. 2The following standard test battery
is recommended based upon the considerations mentioned above:
i)
A test for gene mutation in bacteria.
iii) An in-vivo test for chromosomal
damage using rodent hematopoietic cells. 7
Purpose of genotoxicity
test assays
· Assays allow detection of a drug’s potential for genotoxicity early in development of drug
· Assays designed to be more sensitive to damage in order to
enhance hazard identification.
OECD
test guidelines for genotoxicity and mutagenicity testing 8
· Determine toxicity profiles
of chemicals
· Reveal the molecular
mechanism underlying the chemicals genotoxic and
carcinogenic effects
· Monitor the diseases and
effectiveness of clinical treatments
2. Available
from:URL : http://En.Wikipedia.Org/Wiki/Genotoxicity, accessed on
May, 2014
3. Phillips
DH, Arlt VM. Genotoxicity:
damage to DNA and its consequences. EXS. 2009; 99: 87-110.
10. Suzanne R. Thornton-J. International Research
CMC Conference, Sanofi Aventis, U.S. 2006; 1-8
Received on
12.07.2014 Accepted on 16.08.2014