File Name: micronucleus test and antimutageb.zip
- Antimutagenic compounds and their possible mechanisms of action
- Current Trends and Future Perspectives of Antimutagenic Agents
In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA , of an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer , mutagens are therefore also likely to be carcinogens , although not always necessarily so. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes. Not all mutations are caused by mutagens: so-called "spontaneous mutations" occur due to spontaneous hydrolysis , errors in DNA replication , repair and recombination. The first mutagens to be identified were carcinogens , substances that were shown to be linked to cancer.
Antimutagenic compounds and their possible mechanisms of action
Mutagenicity refers to the induction of permanent changes in the DNA sequence of an organism, which may result in a heritable change in the characteristics of living systems.
Antimutagenic agents are able to counteract the effects of mutagens. This group of agents includes both natural and synthetic compounds. Based on their mechanism of action among antimutagens, several classes of compounds may be distinguished.
These are compounds with antioxidant activity; compounds that inhibit the activation of mutagens; blocking agents; as well as compounds characterized with several modes of action. It was reported previously that several antitumor compounds act through the antimutagenic mechanism. Hence, searching for antimutagenic compounds represents a rapidly expanding field of cancer research.
Thus, the present review attempts to give a brief outline on substances presenting antimutagenic potency and their possible mechanism of action. Additionally, in the present paper, a screening strategy for mutagenicity testing was presented and the characteristics of the most widely used antimutagenicity assays were described. The genomes of all living organisms are constantly subjected to damage by both external agents and endogenous processes, such as spontaneous DNA damage.
Mutations may alter a single gene, a block of genes, or whole chromosomes. Point gene mutations affect only one nucleotide or a few nucleotides within a gene. Point mutations, which are the most common type of alteration in the DNA sequence, can be divided into three main types: a base pair substitution the replacement of one base pair with another ; a deletion the loss of one or more base pairs ; and an insertion the addition of extra base pairs into the DNA sequence. Genotoxic effects on DNA are not always related to mutations Maurici et al.
Mutations are created mainly by external factors, including chemical and physical agents, called mutagens. Additionally, mutations can occur spontaneously due to errors in DNA replication, repair, and recombination.
In general, mutations can be grouped into negative, neutral, positive, lethal, and sub-lethal. Therefore, knowledge on the mode of action of certain mutagenic compounds provides a basis for an explanation of how antimutagenic compounds work. Identifying the antimutagenic compounds is among the most promising area of research in recent years.
Therefore, in this review, the substances presenting antimutagenic activity are presented, with special emphasis on their mechanisms of action Fig.
Moreover, the present paper is concerned with the screening strategy for mutagenicity testing and the most popular assays used in antimutagenicity testing. Consequently, the number of mutation events is increased above the background mutation frequency. As chemical mutagens induce mutations by different mechanisms, several major classes of them, such as alkylating agents, base analogs, and intercalating agents, can be distinguished.
The most frequent location of adducts in DNA is at guanine, leading to the formation of O6-alkylguanine Sanderson and Shield Noteworthy, some of the alkylating agents, such as cyclophosphamide CP , are used for the treatment of cancer.
Base analogs are molecules that have similar structure to normal DNA bases and, thereby, can substitute a base in genetic material, leading to transitions and tautomerization.
For example, 5-bromouracil 5-BU is an analog of thymine, whereas 2-amino-purine 2-AP is an analog of adenine. It should be noted that various base analogs are used as anticancer agents and immunosuppressants. This results in single-nucleotide pair insertions and deletions. Many mutagenizing agents known as direct-acting mutagens. During this process, the transformation of promutagen into the actual mutagen takes place. Certain compounds, known as antimutagens, are able to decrease or even remove the mutagenic effects of potentially harmful chemicals.
According to Kada et al. Desmutagens that function extracellularly are able to inactivate mutagenic agents before they reach DNA. On the other hand, bioantimutagens act within the cell and participate in mutation suppression after DNA damage. These compounds are able to influence genome repair and replication Kada and Shimoi ; De Flora It was reported previously that several antitumor compounds act through the antimutagenic mechanism Tsai et al.
Hence, searching for antimutagenic compounds represents a rapidly expanding field of cancer research Heo et al. Interestingly, certain compounds exhibit dual nature and display both antimutagenic and mutagenic effects.
As many mutagens act through the generation of reactive oxygen species ROS , the removal of reactive molecules represents an important strategy in the process of antimutagenesis Shay et al.
There is increasing evidence that compounds with antioxidant properties can remove ROS before these molecules react with DNA, resulting in a mutation Lee et al. Unal et al. The use of several assays in studies on LA antigenotoxicity revealed the comprehensive action of this compound against genetic damage. These beneficial effects can be primarily attributed to the antioxidant potency of LA. This is consistent with previous reports describing LA as a highly potent antioxidant that plays numerous roles in removing ROS Evans and Goldfine ; Cai et al.
In another study, Nardemir et al. Thus, lichen species may protect DNA from genetic damage through the restoration of natural antioxidant defense mechanisms. Other authors also confirmed that the antimutagenic activity of the lichen extracts is closely related to antioxidant effects Agar et al. Another example of an antimutagen of natural origin acting mainly through its antioxidant properties is Acacia salicina , the extracts of which provide protection against DNA strand scission induced by the hydroxyl radical.
The observed antigenotoxic potency could be ascribed, at least in part, to their antioxidant effects. Some antimutagenic compounds are not potent antioxidants on their own but can be converted into molecules that display antioxidant activity. Such phenomena was observed for several amino acid conjugates of curcumin that demonstrated very high antimutagenic activity with mutagens such as NaN 3 and methyl methanesulfonate MMS against Salmonella typhimurium strains Parvathy et al.
Moreover, the antimutagenic activity of a powder of grain Lisosan G in yeast Saccharomyces cerevisiae was attributed primarily to the antioxidant potency of Lisosan G polyphenols Frassinetti et al. The search for synthetic antimutagens is another important trend in the area of antimutagenicity research. For example, Roy et al. Recently, also, the novel bichalcophenes significantly decreased the mutagenicity induced by two mutagens, namely, NaN 3 and BP El-Sayed and Hussin It was found that the antimutagenic potential of the compounds could be attributed to their antioxidant activity Collins et al.
Based on current knowledge, antioxidant activity is a desirable property, since it can be attributed to the antimutagenic effects of compounds. Thus, it would be vital to test the antimutagenic potential of any compound that displays antioxidant activity.
The mutagenic effect of promutagens is dependent on their metabolic activation, which is mediated mainly by phase I metabolic enzymes, such as the cytochrome P family of enzymes. Some antimutagens are able to inhibit the enzymes responsible for the biotransformation of mutagenic compounds, leading to the inhibition of promutagens bioactivation.
The antimutagenic activity of the tested compounds was probably due to the inhibition of L-azidoalanine and O6-methylguanine formation. With reference to natural antimutagens, Nardemir et al. In another study, phytoconstituents isolated from Terminalia arjuna suppressed the mutagenic effect of the aromatic amine, i. The observed activity was found to be a consequence of the inhibition of the metabolic activation of 2-AF to the mutagenic forms.
The mutagen activation is connected with N-oxidation by cytochrome PA2; next, the activation by N-acetyltransferase takes place Beudot et al. Also, in the case of isothiocyanates, the main mechanism of their antimutagenicity is related to the inhibition of the metabolic activation of mutagens via the influence on cytochrome PA1 and 1A2 activity Hamilton and Teel Another important protective mechanism against chemical mutagenesis is related to the direct chemical interaction between an antimutagenic compound and a mutagen before it induces DNA damage.
In that way, 3-chloro dichloromethyl hydroxy-2 5H -furanone MX was inactivated using various sulfhydryl compounds, such as cysteine Watanabe et al. Blocking agents are also able to prevent mutagenic compounds from reaching target sites. For example, nucleophilic bichalcophenes might be able to bind to DNA and, therefore, protect genetic material from electrophilic mutagenic agents Marnewick et al.
Another hypothesis for bichalcophenes antimutagenic potential might be that these compounds are able to directly interact with mutagens, leading to the inhibition of their damaging activity Watanabe et al. Hour et al. Moreover, it was implied that gallic acid can bind or insert into the outer membrane transporters and lead to the blockage of a mutagen that was transferred into the cytosol. In another study, Acanthopanax divaricatus var.
A great variety of antimutagenic agents act through multiple mechanisms to provide protection against diverse mutagens. Noteworthy, the ability of compounds to affect mutagens simultaneously in several different ways significantly increase antimutagenic effectiveness. Hence, searching for such multifunctionally acting antimutagens is of great importance.
In the study conducted by Ozturkcan et al. The findings of the study provided information about chemical prevention from the toxicity of both mutagens by using selected compounds.
The antimutagenic potential of these compounds may be related to the inhibition of the production of O6-methylguanine, a product of MNNG that is related to its mutagenic effect Eadie et al. In addition, the study showed that both compounds also abolished mutagenesis induced by 9-AA that binds to DNA noncovalently by intercalation. Consequently, frameshift mutations at hotspots are formed, leading to the repetition of a single base, mainly guanine Hoffmann et al.
In another study, Ajith and Janardhanan demonstrated the in vitro antimutagenic activity of ethyl acetate extract of macro fungus, Phellinus rimosus , using the Ames assay. It was concluded that the antimutagenic potential of the extract against direct-acting mutagens may result from the direct inactivation of mutagens. It is probable that, due to stimulation of the transmembrane export system in bacteria, mutagenic compounds are removed from the cells before they influence the DNA structure.
Additionally, in the case of doxorubicin DXN , the extract of P. The antimutagenic effect of the extract against indirect-acting mutagen BP may be partially ascribed to the inhibition of the mixed-function oxidase MFO system and also to the conjugation of the components of the extract with benzo[a]pyrene-7,8-diol-9,epoxide BPDE , being a BP-active mutagen. Moreover, the inhibition of 2-AF-induced mutagenesis might be related to the MFO inhibition or inactivation of the reactive carcinogenic ester of 2-AF, namely, 2-acetylaminofluorene-N-sulfate, which is capable of attacking guanine residues in nucleic acids.
In case of both types of mutagens direct and indirect , the extract of P. Boubaker et al. Chloroform extract was antimutagenic against both direct- and indirect-acting mutagens, as the extract may serve as a blocking agent that is capable of influencing the activities of enzymes engaged in the metabolism of mutagens and carcinogens. In another study, Morffi et al.
MSBE is a Cuban nutraceutical supplement rich in polyphenols. It was observed that MSBE protected against genetic material damage induced by all the tested mutagens, except for NaN 3. Pesarini et al. It was demonstrated that phytic acid may intercept carcinogenic azoxymethane, inhibiting it even before it can damage DNA. Moreover, antioxidants included in wheat bran are able to modulate DNA repair enzymes. In the case of heterocyclic aromatic amines HAAs , it was proved that the attenuation of their unfavorable mutagenic effect might result from the influence on the DNA repair pathway, the stimulation of detoxifying enzymes, and the inhibition of enzymes that participate in the metabolic activation of HAAs Schwab et al.
Current Trends and Future Perspectives of Antimutagenic Agents
Assessment of mutagenic, antimutagenic and genotoxicity effects of Mimosa tenuiflora. Viviane A. Pereira II ; Isis F. Freitas II ; Margareth F. Diniz I ; Hilzeth L.
Several scientific studies have shown that 6-MITC possesses interesting antimicrobial, anti-inflammatory, antiplatelet and antioxidant properties which therefore suggested us it could have an interesting chemopreventive potential. In a recent publication, we demonstrated, in two different leukemia cell lines, its ability to modulate several mechanisms supporting its antitumor activity. For this reason, we thought useful to continue the research, by investigating the potential antimutagenic activity of 6-MITC and thus better define its profile as a possible chemopreventive agent. The results showed a different behavior of the isothiocyante. Overall, the results obtained suggest a potential antimutagenic activity of 6-MITC, in particular against the aneuploidogen agents. This ability, to inhibit or counteract the mutations at the cellular level has a great therapeutic value and it represents a mechanism through a chemopreventive agent can express its activity.
Irene M. Villasenor, Deborah A. Edu, John B. An antimutagenic compound was isolated from the leaves of Carmona retusa Vahl Masam. Most users should sign in with their email address.
Irene M. Villasenor, Paul Finch, Clara Y. A mutagenic compound was isolated from roasted seeds of Moringa oleifera Lam.
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