Review on Genotoxicity, its Molecular Mechanisms and ...

1 Int. J. Pharm. Sci. Rev. Res., 22(1), Sep Oct 2013; n 43, 236-243 ISSN 0976 044X. Review Article Review on genotoxicity , its Molecular Mechanisms and Prevention Nagarathna , M. Johnson Wesley*, P. Sriram Reddy, Reena. K. Department of Pharmacology, Karnataka College of Pharmacy, Bangalore, 560064, Karnataka, India. *Corresponding author's E-mail: Accepted on: 04-07-2013; Finalized on: 31-08-2013. ABSTRACT. Genotoxicity has become a major problem for the cause of many cancers. In this article we discuss about the basics of genotoxicity, the chemicals which cause these genetic damage and also their mechanism of action. Some in vitro and in vivo methods for measuring the extend of genotoxicity have also been discussed such as chromosomal aberration test and micronucleus assay. Finally a brief account on the drugs being used in present days, and also some plant products which show anti mutagenic effects have been emphasized. Keywords: Genotoxicity, Mutagen, Mutations, Aberrations.

2 INTRODUCTION however, the damage may not always be fixed leading 4. to mutagenesis . A ll chemicals that produce DNA damage leading to mutation or cancer are described as genotoxic. Toxicological studies have undergone a significant evolution during the past decade, with much greater emphasis being placed on chronic toxicity, To assay for genotoxic molecules, researchers assay for DNA damage in cells exposed to the toxic substrates. This DNA damage can be in the form of single and double strand breaks, loss of excision repair, cross-linking, alkali- carcinogenicity, teratogenicity and mutagenicity. The labile sites, point mutations, and structural and numerical mutations in somatic cells are not only involved in the chromosomal aberrations. The compromised integrity of carcinogenesis process but also play a role in the the genetic material has been known to cause cancer. pathogenesis of other chronic degenerative diseases, Consequently, many sophisticated techniques including such as atherosclerosis and heart diseases, which are the Ames Assay, in vitro and in vivo Toxicology Tests, and leading causes of death in the human population1,2.

3 Comet Assay have been developed to assess the Micronucleus test and chromosomal aberration test are chemicals' potential to cause DNA damage that may lead used for studying antimutagenic activity of a drug. One of to cancer. the best ways to minimize the effect of mutagens and Anti mutagen is described as an agent that reduces the carcinogens is to identify the anticlastogens/. apparent yield of spontaneous and /or induced antimutagens (substances which suppress or inhibit the mutations. Mechanisms of anti mutagenesis have been process of mutagenesis by acting directly on the classified into two major processes one is mechanism of cell) and desmutagens (substances which desmutagenesis: in which factors act directly on somehow destroy or inactivate, partially or fully the mutagens or inactivate them. The other is bio- mutagens, thereby affecting less cell population) in our antimutagenesis in which factors act on the processes of diets and increasing their use.

4 Nature has bestowed us mutagenesis or repair DNA damages that result in a with medicinal plants. There is a need to explore them for decrease in the mutation frequency. Gemcitabine used as use as antimutagenic and anticarcinogenic food or drug a mutagen with anti-metabolites activity, it exerts its additives. effect by prohibiting DNA chain elongation. In genetics, genotoxicity describes the property of Antimutagenesis are considered as one of the most chemical agents that damages the genetic information feasible ways for inhibiting the negative effects of within a cell causing mutations, which may lead to cancer. environmental genotoxicants including carcinogens. While genotoxicity is often confused with mutagenicity, it Nowadays a large number of anti-mutagens of plants 5. is important to note that all mutagens are genotoxic, origins are known . Evaluation of genetic toxicity is an however, not all genotoxic substances are mutagenic.

5 The important component of the safety assessment of alteration can have direct or indirect effects on the DNA: chemicals, including pharmaceuticals, agricultural the induction of mutations, mistimed event activation, chemicals, food, additives and industrial chemicals. Up to and direct DNA damage leading to mutations3. The the present time, genotoxicity has been regulated mainly permanent, hereditary changes can affect either somatic on the basis of qualitative outcomes of hazard cells of the organism or germ cells to be passed on to identification assays, decisions are often based on future generations. Cells prevent expression of the classification as positive or negative for genotoxic genotoxic mutation by either DNA repair or apoptosis; potential. Most human carcinogens are identified by epidemiological studies. These studies are necessarily International Journal of Pharmaceutical Sciences Review and Research Available online at 236.

6 Int. J. Pharm. Sci. Rev. Res., 22(1), Sep Oct 2013; n 43, 236-243 ISSN 0976 044X. long term, as no effect is expected to be observed until ANTI-MUTAGEN. decades after the carcinogenic event or events Anti-mutagen is described as an agent that reduces the convincing, these studies are costly and exposure levels apparent yield of spontaneous and induced mutations. and effects are difficult to quantify. A few multiple Mechanisms of anti-mutagenesis have been classified into generation mutation assays have been carried out using two major processes one is desmutagenesis: in which rodents: factors on mutagens or inactivate them. The other is bio- Dominant lethal antimutagenesis in which factors act on the processes of Mouse spot test mutagenesis or repair DNA damages that result in a decrease in the mutation frequency. Gemcitabine used as Heritable translocation test a mutagen with anti-metabolites activity, exerts its effect These tests must be carried out on a large scale, and tend by prohibiting DNA chain elongation8.

7 To be insensitive; in order to detect a 1% increase (which Molecular Mechanisms involved in production of is a very strong effect) in carcinogenicity in a human chromosomal aberrations population, one would need to perform an animal study to such a large scale as to cost over 25 million dollars. One of the endpoints of genotoxicity is gene mutations. Genotoxicity tests can be defined as in vitro and in vivo Mutagenic chemicals cause predominantly gene tests designed to detect compounds that induce genetic mutations, which are generally not lethal but can form a damage by various Mechanisms . These tests enable major threat to the integrity of chromosomes and viability hazard identification with respect to damage to DNA and of cells. Fortunately, cells are equipped with several DNA. its fixation. Fixation of damage to DNA in the form of repair systems. Depending on the specific classes of DNA. gene mutations, larger scale chromosomal damage or lesions, one or more DNA repair pathways become recombination is generally considered to be essential for active9.

8 Four of the 5 major DNA repair pathways are heritable effects and in the multi-step process of involved in the repair of DNA lesions leading to gene malignancy, a complex process in which genetic changes mutations: direct repair, base excision repair (BER), may play only a part. Numerical chromosome changes nucleotide excisions repair (NER) and mismatch repair10. have also been associated with tumour genesis and can The 5th major repair pathway involved is single/double indicate a potential for aneuploidy in germ cells. strand break repair. Compounds that are positive in tests that detect such a. Direct repair kinds of damage have the potential to be human carcinogens and/or mutagens. Because the relationship Direct repair acts by removing or reversing the DNA. between exposure to particular chemicals and lesions by a single enzyme reaction in a basically error- carcinogenesis is established for humans, whilst a similar free manner and with high substrate specificity.

9 This relationship has been difficult to prove for heritable mechanism does not require a template, since the diseases, genotoxicity tests have been used mainly for the damage they restore only occurs in one base and there is prediction of carcinogenicity. Nevertheless, because germ no involvement of incision of the sugar-phosphate line mutations are clearly associated with human disease, backbone or base excision. These lesions can occur due to the suspicion that a compound might induce heritable alkylating agents. Direct repair is carried out by specific effects is considered to be just as serious as the suspicion enzymes called alkyl guanine-DNA methyl transferases that a compound might induce cancer. In addition, the (AGMT), which remove the alkyl group from the guanine outcome of genotoxicity tests can be valuable for the residue of DNA and transfers it to one of its own cysteine interpretation of carcinogenicity studies 7. residues.

10 Next to AGMT, in bacteria and yeast, photolyases can directly reverse UV-induced DNA. Mutations are changes in the DNA sequence of a cell's damage 11-13.. genome and are caused by radiation, viruses, transposons and mutagenic chemicals, as well as errors that occur b. Base excision repair (BER). during meiosis or DNA replication. There is no consensus Base excision repair (BER) is a cellular mechanism that among genetic toxicologists regarding the classification of repairs damaged DNA throughout the cell cycle. This mutations. mechanism protects cells from the deleterious effects of Three groups of mutations can be distinguished: endogenous DNA damage induced by hydrolysis, reactive oxygen species and other intracellular metabolites, and is 1. Single point mutations or Gene mutations: These are also responsible for the removal of many lesions induced small changes in the DNA at the level of the bases and by ionizing radiation and strong alkylating agents.