Global journal of
Pharmacy & pharmaceutical Science
ISSN:2573-2250
Review Article Glob J Pharmaceu Sci
Volume 1 Issue 5 - April 2017
DOI: 10.19080/GJPPS.2017.02.555575 Copyright © All rights are reserved by Rajendra SV
Genotoxicity: Mechanisms, Testing Guidelines and
Methods
Mohamed SAKS, Sabita Upreti, Rajendra SV* and Raman Dang
Krupanidhi College of Pharmacy, India
Submission: March 08, 2017; Published: April 27, 2017
*Corresponding author: Rajendra SV, Department of Pharmacology, Krupanidhi College of Pharmacy, India, Tel: ;
Email:
Abstract
Genotoxicity is one of the major causes for cancer. Genotoxins are agents that can cause the damage of DNA or chromosomal structure
thereby causing mutations. It can be chemical or radiation. This damage in the somatic cells will lead to various diseases ranging to cancer
whereas the damage to the germ cell will lead to heritable diseases. Better identification and understanding of genotoxins would enable us to
prevent the potential damage that can be caused by these genotoxic agents. In this article we discuss about the basic of genotoxicity and the
importance of genotoxic studies.
Keywords: Genotoxins, Mutagens, DNA Damage, Chromosomal mutation, Testing guidelines.
Introduction
[3,4] One of the best ways to control the damage due to mutagens
Genotoxicity is a word used in genetics that describes the
and carcinogens is to identify the substance or chemical, i.e.
possession of substance that has destructive effect on the genetic
antimutagens /anticlastogens (which suppress or inhibit the
material of the cell (DNA, RNA) thus affecting the integrity of
mutagenesis process by directly acting on the cell mechanism)
the cell. Genotoxins are mutagens that can cause genotoxicity
and demutagens (which destroy or inactivate the mutagens
leading to the damage of DNA or chromosomal material thus
partially or fully thereby affecting less population of cell) from
causing mutation. Genotoxins can include chemical substance as
the medicinal plants so that it can be used as antimutagenic and
well as radiation. Genetic toxicology is the branch of science that
anticarcinogenic food or drug additives [5-7].
deals with the study of agents or substances that can damage the
cell’s DNA and chromosomes. It is noted that often genotoxicity
is confused with mutagenicity. All mutagens are genotoxic
however all genotoxic substances are not mutagenic [1].
Genotoxins can be of the following category depending on
its effects [2]:
o Carcinogens or cancer causing agents
o Mutagens or mutation causing agents
o Teratogens or birth defect causing agents
The damage of genetic material of somatic cells may lead
to malignancy (cancer) in eukaryotic organisms. Whereas
the genetic damage of the germ cells may lead to heritable
mutations causing birth defects (Figure 1). Mutations can be of
any form; which may include duplication, insertion or deletion
of genetic information. These mutations can cause varying range Figure 1: Risk of genotoxicity [3].
of problems in the host, from a wide variety of diseases to cancer
Glob J Pharmaceu Sci 1(5): GJPPS.MS.ID.555575 (2017) 001
, Global Journal of Pharmacy & Pharmaceutical Sciences
Importance of genotoxicity studies Iarc (International Agency For Research On Cancer)
classification of carcinogens [4]
Genotoxicity studies can be defined as various in-vitro and
in-vivo tests designed to identify any substance or compounds o IARC class 1-The substance is carcinogenic to humans.
which may induce damage to genetic material either directly or
o IARC class 2A-The substance is probably carcinogenic
indirectly by various mechanisms. These tests should enable the
to humans.
identification of hazard with respect to DNA damage and fixation
[8]. Genetic change play only a part in the complex process of o IARC class 2B-The substance is possibly carcinogenic to
heritable effects and malignancy which include the fixation of the humans.
damage to the DNA by gene mutation or large scale chromosomal
o IARC class 3-The substance is not classifiable to as to its
damage or recombination or numerical chromosomal changes.
carcinogenicity to humans.
These tests play an important role in predicting if the compound
have the potential to cause genotoxicity and carcinogenicity by o IARC class 4-The substance is probably not carcinogenic
testing them positive [9]. As a part of safety evaluation process, to humans.
regulatory authorities all over the globe require information on Agents that can cause direct or indirect damage to the
the genotoxic potential of the new drugs. Genotoxicity is usually DNA
evaluated along with other toxicological end points during the
safety assessment [10] (Figure 2). Reactive oxygen species are known to be genotoxic in
nature, thus any chemical or substance that may increase the
reactive oxygen species (ROS) production might evidently add
to the endogenously produced ROS and may lead to non-linear
relationships of dose-effect. The following agents are capable of
damaging the DNA directly or indirectly; [14]
o Electrophilic species that form covalent adducts to the
DNA
o Reactive oxygen species
o Ultra violet and ionizing radiations.
o Nucleoside analogues
o Topoisomerase inhibitors
Figure 2: Relationship between genotoxicity and carcinogenicity
[12]. o Protein synthesis inhibitors
During the early testing stages; the same testing assays are o Some herbal plants like Aconite, Alfa-alfa, Calamus,
carried out for predicting both the potential heritable germ cell Aloe vera, Isabghol etc.
damage as well as the carcinogenicity because these endpoints Anti-mutagen is any agent that decreases the effect of
have common precursors. The relationship between exposure spontaneous and induced mutations. There are mainly two
to particular chemical and carcinogenesis has been established mechanisms of anti-mutagenesis:
whereas such relationship has been difficult to establish
for heritable diseases, genotoxic studies have been mainly a. Desmutagenesis in which the factors on the mutagens
associated and used for the prediction of carcinogenicity of a are somehow inactivated,
compound [11,12] b. Bio-antimutagenesis, in which the factors act on the
Classifiaction of carcinogens process of mutagenesis or by repairing the damaged DNA
that result in the decreased frequency of DNA mutation [15].
EU classification of carcinogens [13]
Our cells have several DNA repair system by which they try
o Carcinogen category 1-shown to cause cancer in to control the DNA mutations naturally.
humans
The five major pathways through which the cell repair the
o Carcinogen category 2-causes cancer in animal tests, damaged DNA are: [16-19]
and most probably also in humans
o Direct repair
o Carcinogen category 3-possibly carcinogenic, but
o Base excision repair( BER)
evidence supporting carcinogenicity is inadequate for the
classification to category 2. o Nucleotide excision repair (NER)
How to cite this article: Mohamed S, Sabita U, Rajendra S, Raman D. Genotoxicity: Mechanisms, Testing Guidelines and Methods. Glob J Pharmaceu
002 Sci. 2017; 1(5) : 555575. DOI: 10.19080/GJPPS.2017.02.555575
Pharmacy & pharmaceutical Science
ISSN:2573-2250
Review Article Glob J Pharmaceu Sci
Volume 1 Issue 5 - April 2017
DOI: 10.19080/GJPPS.2017.02.555575 Copyright © All rights are reserved by Rajendra SV
Genotoxicity: Mechanisms, Testing Guidelines and
Methods
Mohamed SAKS, Sabita Upreti, Rajendra SV* and Raman Dang
Krupanidhi College of Pharmacy, India
Submission: March 08, 2017; Published: April 27, 2017
*Corresponding author: Rajendra SV, Department of Pharmacology, Krupanidhi College of Pharmacy, India, Tel: ;
Email:
Abstract
Genotoxicity is one of the major causes for cancer. Genotoxins are agents that can cause the damage of DNA or chromosomal structure
thereby causing mutations. It can be chemical or radiation. This damage in the somatic cells will lead to various diseases ranging to cancer
whereas the damage to the germ cell will lead to heritable diseases. Better identification and understanding of genotoxins would enable us to
prevent the potential damage that can be caused by these genotoxic agents. In this article we discuss about the basic of genotoxicity and the
importance of genotoxic studies.
Keywords: Genotoxins, Mutagens, DNA Damage, Chromosomal mutation, Testing guidelines.
Introduction
[3,4] One of the best ways to control the damage due to mutagens
Genotoxicity is a word used in genetics that describes the
and carcinogens is to identify the substance or chemical, i.e.
possession of substance that has destructive effect on the genetic
antimutagens /anticlastogens (which suppress or inhibit the
material of the cell (DNA, RNA) thus affecting the integrity of
mutagenesis process by directly acting on the cell mechanism)
the cell. Genotoxins are mutagens that can cause genotoxicity
and demutagens (which destroy or inactivate the mutagens
leading to the damage of DNA or chromosomal material thus
partially or fully thereby affecting less population of cell) from
causing mutation. Genotoxins can include chemical substance as
the medicinal plants so that it can be used as antimutagenic and
well as radiation. Genetic toxicology is the branch of science that
anticarcinogenic food or drug additives [5-7].
deals with the study of agents or substances that can damage the
cell’s DNA and chromosomes. It is noted that often genotoxicity
is confused with mutagenicity. All mutagens are genotoxic
however all genotoxic substances are not mutagenic [1].
Genotoxins can be of the following category depending on
its effects [2]:
o Carcinogens or cancer causing agents
o Mutagens or mutation causing agents
o Teratogens or birth defect causing agents
The damage of genetic material of somatic cells may lead
to malignancy (cancer) in eukaryotic organisms. Whereas
the genetic damage of the germ cells may lead to heritable
mutations causing birth defects (Figure 1). Mutations can be of
any form; which may include duplication, insertion or deletion
of genetic information. These mutations can cause varying range Figure 1: Risk of genotoxicity [3].
of problems in the host, from a wide variety of diseases to cancer
Glob J Pharmaceu Sci 1(5): GJPPS.MS.ID.555575 (2017) 001
, Global Journal of Pharmacy & Pharmaceutical Sciences
Importance of genotoxicity studies Iarc (International Agency For Research On Cancer)
classification of carcinogens [4]
Genotoxicity studies can be defined as various in-vitro and
in-vivo tests designed to identify any substance or compounds o IARC class 1-The substance is carcinogenic to humans.
which may induce damage to genetic material either directly or
o IARC class 2A-The substance is probably carcinogenic
indirectly by various mechanisms. These tests should enable the
to humans.
identification of hazard with respect to DNA damage and fixation
[8]. Genetic change play only a part in the complex process of o IARC class 2B-The substance is possibly carcinogenic to
heritable effects and malignancy which include the fixation of the humans.
damage to the DNA by gene mutation or large scale chromosomal
o IARC class 3-The substance is not classifiable to as to its
damage or recombination or numerical chromosomal changes.
carcinogenicity to humans.
These tests play an important role in predicting if the compound
have the potential to cause genotoxicity and carcinogenicity by o IARC class 4-The substance is probably not carcinogenic
testing them positive [9]. As a part of safety evaluation process, to humans.
regulatory authorities all over the globe require information on Agents that can cause direct or indirect damage to the
the genotoxic potential of the new drugs. Genotoxicity is usually DNA
evaluated along with other toxicological end points during the
safety assessment [10] (Figure 2). Reactive oxygen species are known to be genotoxic in
nature, thus any chemical or substance that may increase the
reactive oxygen species (ROS) production might evidently add
to the endogenously produced ROS and may lead to non-linear
relationships of dose-effect. The following agents are capable of
damaging the DNA directly or indirectly; [14]
o Electrophilic species that form covalent adducts to the
DNA
o Reactive oxygen species
o Ultra violet and ionizing radiations.
o Nucleoside analogues
o Topoisomerase inhibitors
Figure 2: Relationship between genotoxicity and carcinogenicity
[12]. o Protein synthesis inhibitors
During the early testing stages; the same testing assays are o Some herbal plants like Aconite, Alfa-alfa, Calamus,
carried out for predicting both the potential heritable germ cell Aloe vera, Isabghol etc.
damage as well as the carcinogenicity because these endpoints Anti-mutagen is any agent that decreases the effect of
have common precursors. The relationship between exposure spontaneous and induced mutations. There are mainly two
to particular chemical and carcinogenesis has been established mechanisms of anti-mutagenesis:
whereas such relationship has been difficult to establish
for heritable diseases, genotoxic studies have been mainly a. Desmutagenesis in which the factors on the mutagens
associated and used for the prediction of carcinogenicity of a are somehow inactivated,
compound [11,12] b. Bio-antimutagenesis, in which the factors act on the
Classifiaction of carcinogens process of mutagenesis or by repairing the damaged DNA
that result in the decreased frequency of DNA mutation [15].
EU classification of carcinogens [13]
Our cells have several DNA repair system by which they try
o Carcinogen category 1-shown to cause cancer in to control the DNA mutations naturally.
humans
The five major pathways through which the cell repair the
o Carcinogen category 2-causes cancer in animal tests, damaged DNA are: [16-19]
and most probably also in humans
o Direct repair
o Carcinogen category 3-possibly carcinogenic, but
o Base excision repair( BER)
evidence supporting carcinogenicity is inadequate for the
classification to category 2. o Nucleotide excision repair (NER)
How to cite this article: Mohamed S, Sabita U, Rajendra S, Raman D. Genotoxicity: Mechanisms, Testing Guidelines and Methods. Glob J Pharmaceu
002 Sci. 2017; 1(5) : 555575. DOI: 10.19080/GJPPS.2017.02.555575
