Natural Antimutagens: A Review
Mutagens are not only involved in genotoxicity and carcinogenesis but also involved in the inception and pathogenesis of several chronic degenerative diseases including hepatic disorders, neurodegenerative disorders, cardiovascular disorders, diabetes, arthritis, chronic inflammation and in the process of ageing. One of the best ways to minimize the detrimental effects of mutagens is by the use of natural antimutagens. Naturally occurring antimutagenic principles present in plants, human diet and other sources have protective effects against mutagens. These include flavonoids, phenolics, coumarins, carotenoids, anthraquinones, tannins, saponins and many more. Present review attempts to furnish a brief overview on natural products conferring antimutagenicity.
February 27, 2010; Accepted: April 04, 2010;
Published: July 17, 2010
Mutations are the cause of innate metabolic defects in cellular systems, triggering
morbidity and mortality in living organisms. A plethora of synthetic and natural
substances, apart from various genotoxic physical and biological agents are
known to act as mutagenic, co-carcinogenic and/or carcinogenic agents. There
is increasing evidence that mutation in somatic cells are not only involved
in the carcinogenesis but can also cause genetic disorders like atherosclerosis,
heart diseases and several other degenerative disorders (De
Flora et al., 1996). Since, the mutagens are involved in the initiation
and promotion of several human diseases, including cancer, the significance
of novel bioactive phytocompounds in counteracting these pro-mutagenic and carcinogenic
effects is now gaining credence. Such chemicals that reduce the mutagenicity
of physical and chemical mutagens are referred to as antimutagens (Mitscher
et al., 1986).
Numerous studies have been carried out in last four decades in order to identify
compounds that might protect humans against DNA damage and its consequences.
There are continued efforts all over the world to explore the rich biodiversity
of edible as well as medicinal plants and other edible non-toxic plants in pursuit
of the most effective phytoantimutagens. These bioactive compounds belong to
a variety of different chemical groups such as phenolics, pigments, allylsulfides,
glucosinolates, tannins, anthocyans, flavonoids, phytosterols, protease inhibitors
and phytoestrogens. Many of these substances elicit, apart from their antimutagenic
and anticarcinogenic properties, additional beneficial effects such as activation
of the immune system and/or protection against cardiovascular diseases (Middleton
and Kandaswami, 1993).
The group of chemicals that cause cancer in man and animals are collectively
referred to as carcinogens. Environmental pollution is associated with increased
risk of cancer. Prevention of cancer and other mutation related diseases can
be pursued by avoiding exposure to recognized carcinogens or mutagens, by favoring
the intake of protective factors and by fortifying physiological defense mechanism.
Moreover, there is an increasing awareness that certain naturally occurring
substances in plants and other source have protective effects against environmental
mutagens or carcinogens and also endogenous mutagens. Hence, research work related
to the discovery, characterization and use of antimutagenic agents is receiving
considerable attention. A large number of experimental reports have begun to
appear in the scientific literature, wherein increasingly more natural antimutagens
have been identified, isolated and found to possess significant mutation chemoprevention
properties. In this review promise of these natural antimutagens has been focused
MUTATION, MUTAGENS AND ANTIMUTAGENS
Mutation: Mutation refers to heritable change in nucleotide sequence
or number occurring due to alteration in the sequence of the code in a gene
due to change, removal or insertion of one or more bases in a gene resulting
in an altered gene product (Hartl et al., 1994).
This change may be expressed, for example as change in the structure of a protein
which alters or abolishes its enzymatic properties. Mutation occurs spontaneously
or may be induced by several physical, chemical or biological agents. In general,
mutations are detrimental because in most cases they lead to defects in cellular
functions. Mutations cause permanent alteration in DNA structure, which have
been implicated in the etiopathology of cancer and other degenerative diseases.
The chemical and physical factors that induce mutation are called mutagens and
those that reduce their mutagenicity are called antimutagens (Venitt
and Parry, 1984).
Mutagens: The substances which can induce mutations are known as mutagens.
These include, physical agents like Ultra Violet (UV) and X-rays which cause
the deletion of nucleotide. These agents produce a variety of lesions in DNA
including strand break, base damage and dimerisation of bases. Many diverse
environmental, industrial, dietary and natural chemicals are capable of inducing
mutation and genotoxic effects. There is evidence that mutation in somatic cells
causes cancer, genetic disorders and many other degenerative disorders including
arthritis and connective tissue disorders, hepatic disorders, neurodegenerative
disorders, cardiovascular disorders, diabetes, chronic inflammation, ageing
etc. The mutagenic effects of genotoxic chemicals are additive, cumulative and
sometimes irreversible (Hartl et al., 1994).
Antimutagens: An antimutagen can prevent the transformation of a mutagenic
compound into mutagen, inactivate the mutagen or otherwise prevent the reaction
between mutagen and DNA. Another kind of antimutagens may induce, repress or
inactivate directly or indirectly the enzymes of the DNA repair recombination
and replication pathways. The antimutagens can be classified as: desmutagens
and bio-antimutagens (Ferguson, 1994).
Desmutagens: These are substances, which inactivate the mutagens partially or fully by enzymatic or chemical interaction before the mutagen attacks the genes. These must be considered only as apparent antimutagens.
Bio-antimutagens: These are regarded as true antimutagens. They suppress the process of mutation after genes are damaged by mutagens. They act on the repair and replication processes of the mutagen damaged DNA resulting in a decline in mutation frequency.
MECHANISM OF ANTIMUTAGENESIS
The major mechanisms of antimutagenesis can be broadly described as under (De
Flora et al., 1992):
||Chemical or enzymatic inactivation
||Prevention of formation of active species
||Antioxidant free radical scavenging
Chemical or enzymatic inactivation: Many mutagens, which are reactive, acting not only on DNA but also on proteins and enzymes can be directly inactivated by a range of different chemicals. Antimutagenic and anticarcinogenic properties have been associated with both inhibitors and inducers of cytochrome P-450 enzymes such as indole-3-carbinol. Inducers of phase-II metabolic enzymes such as glutathione transferase tend to inhabit a wide range of target carcinogens e.g., isothiocyanates such as benzyl isothiocyanate and antioxidants such as 2, 3-tert butyl-4-hydroxy-anisole (BHA).
Prevention of formation of active species: Many genotoxic mutagens or carcinogens require metabolic activation or bio-activation to an electrophilic from (the active species) that can react with the DNA. Although these processes commonly occur in the liver, there is increasing evidence for metabolic activation by other tissues also, especially for the GIT. N-nitro compounds are often formed in the stomach through a reaction form nitrite and secondary or tertiary amines.
Scavenging: A number of desmutagens are able to scavenge dietary mutagens through binding or adsorption . In general the mutagen remains intact during this process but is unable to react with DNA. Chlorophyllin and some dietary fibers appear to act in this way.
Antioxidant and free radical scavenging: Free radicals can damage DNA and cause mutagenicity and cytotoxicity and thus play a key role in carcinogenesis. It is believed that Reactive Oxygen Species (ROS) can induce mutations and inhibit DNA repair process, that result in the inactivation of certain tumor suppressor genes, leading to cancer. A wide range of antimutagenic agents have antioxidant or free radical scavenging activity e.g., carotenoids, flavonoids and phenolic compounds. These agents can readily scavenge most free radicals especially those having a short half life e.g., OH radical.
JANUS CARCINOGENS AND MUTAGENS
Many substances reported to be antimutagens have themselves been shown to be
promutagenic or carcinogenic. Chemicals belonging to such a category are termed
Janus carcinogens and mutagens after the ancient Roman God Janus who had been
depicted as having one head with two faces, one looking forward and one looking
backward. Several other recent reports have also addressed or emphasized the
biphasic nature of many active substance reported to modulate the mutagenicity
or carcinogenicity of heterocyclic amines. The majority of these modulating
substances are plant products or extracts. Extensive study of the antimutagenicity
literature by Waters et al. (1996) showed that
a number of chemicals have both antimutagenic mutagenic effects. For instance,
β-carotene was the first presumptive anticarcinogen to be included in large-scale,
clinical intervention trials, but the trials were terminated prematurely upon
revelation that β-carotene treatment was associated with an increased cancer
incidence rather than the expected decrease. Other examples include, testosterone,
β-oestradiol, diethylstilbesterol, vanillin etc.
NATURAL ANTIMUTAGENIC AGENTS
Extensive research in the last few decades on the detection and characterization
of antimutagenic compounds from edible, non-edible and medicinal plants and
marine organisms has demonstrated a great diversity. Several authors have suggested
that natural antimutagens may belong to any of the following major class of
compounds. Major emphasis has been laid on the flavonoids, phenolics, carotenoids,
coumarins, anthraquinones, tannins, terpenoids, saponins and several others
all of which are secondary plant metabolites. More than 500 compounds belonging
to at least 25 chemical classes have been recognized as possessing antimutagenic/protective
effects (Boone et al., 1990). In recent years,
there has been an increased interest in identifying the antimutagenic and anticarcinogenic
constituents of both dietary and medicinal plants all over the world. The major
classes of antimutagenic compounds are briefly described below.
Vitamins: Vitamins have been extensively studied for their antimutagenic
potential. Vitamin C and E have been shown to be antimutagenic against doxorubicin
induced chromosomal aberrations (Antunes and Takahashi,
1998). Vitamin A, C and E were found to be antimutagenic towards Methyl
Azoxy Methanol (MAM) induced mutagenesis in Salmonella typhimurium strain
TA100 (Tavan et al., 1997). Vitamin C (ascorbic
acid) when administered concurrently with a pesticide showed significant decrease
in the frequency of pesticide induced mutations (Kuroda,
Flavonoids: Flavonoids are a class of phytochemicals that possess antimutagenic
properties in addition to a wide range of biological activities. Flavonoids
present an important class of antimutagens and anticarcinogens with high potential.
Distinct structure activity relationship were detected when 56 flavonoids, 32
coumarins, 5 naphthoquinones and 12 anthraquinones were tested for their antimutagenic
potencies, with respect to mutagenesis induced by 2-nitrofluoro 3-nitro fluoranthene
and 1-nitropyrene in S. typhimurium TA98. Among flavonoids, all flavones
and many flavonoids with phenolic hydroxyl group like leuteolin, kaempherol
etc., exerted antimutagenicity chalcones and dihydrochaleones were potent antimutagens
(Edenharder and Tang, 1997).
A number of known flavonoids including flavonoid glycosides and isoflavones
were reported to possess significant antimutagenic activity. Citrus juice flavonoids
are reported to possess anticarcinogenic and antimutagenic properties (Calomme
et al., 1996). Heo et al. (1992) tested
14 flavonoids including flavones and flavonol derivatives for their antimutagenic
effect against induction of micronuclei by benzo[α]pyrene (Bap) in polychromatic
erythrocytes (PCEs) of mice.
Isolation of two new isoflavones, fremontin and fremontone from the root of
Psorothamnus fremontii was reported, which are highly active in the inhibition
of mutagenicity of Ethyl Methane Sulfonate (EMS) at all concentrations tested
(Manikumar et al., 1989). Antimutagenic effect
of hispidulin and hortensin, the flavonoids from Millingtonia hortensis
was seen when tested against 2-amino anthracene, aflatoxin B1 induced
mutation (Chulasiri et al., 1992). Other flavonoids
include glaberene from Glycyrrhiza glabra, quercetin, myricetin, kaemferol,
hesperidin and other flavonoids isolated from Ocimum javonica. Antimutagenic
activity all these flavonoids has been tested using S. typhimuricem against
various types of mutagens (Shankel et al., 2000).
Phenolic compounds: Phenolic compounds are a widely studied group of
compounds from natural food and medicinal plants and are also implicated in
various biological activities. Certain phenolic compounds such as ellagic acid
found in strawberries, raspberries, grapes, walnuts, etc. have been found to
be antimutagenic (Loarca-Pina et al., 1996).
Also, the compounds such as epicatechin, (-)-epicatechin gallate, (-)-epigallocatechins,
(-)-epigallocatechin gallate have been reported to be responsible for the antimutagenic
activity of green tea and black tea (Hour et al.,
1999; Weisburger et al., 1996). Ohe
et al. (2001) studied the antigenotoxic properties of tea leaf extracts
in a Salmonella umu-test. Geetha et al. (2004)
demonstrated the antimutagenic activity of green tea catechins against oxidative
mutagens such as tertiary butyl hydroxide, hydrogen peroxide using Salmonella
typhimurium 102 tester strains. Antimutagenic effect of green tea against
smoke-induced mutations in humans were investigated by Lee
et al. (1997) and it was found that green tea can block the cigarette
smoking-induced increase in sister chromatid exchange frequency.
Phenolics present in turmeric and clove, namely curcumin and eugenol respectively
were found to inhibit the mutagenicity produced by direct acting mutagens such
as N-methyl-N'-nitro-N-nitrosoguanidine using S. typhimuricem strains
TA100 and TA1535 and eugenol inhibited tobacco-induced mutagenesis in Ames test
(Soudamini et al., 1995).
Anthraquinones: The antimutagenic activity of anthraquinones (aloe-emodin-anthraquinone
isolated from Aloe barborescence), were reported (Shankel
et al., 2000). Among compounds structurally related to anthraquinones,
anthrone, acridone and xanthone exerted antimutagenecity, anthrone being the
most patent one. All naphthaquinones were potent antimutagens, plumbagin and
2-methyl-5-hydroxy naphthoquinone showed exceptional antimutagenicity (Edenharder
and Tang, 1997).
Carotenoids: Several studies on carotenoids have shown that they affect
activation of promutagens. The water insoluble residues of some carotenoid rich
fruits and vegetables such as apricots, arranges, brussels, sprouts, carrots,
yellow-red peppers and tomatoes when sequentially extracted with several solvents
and tested for inhibition of mutagenicities induced by aflatoxin B1,
benzo[α]pyrene (BaP), imidazoquinoline and cyclophosphamide (CP) in histidine
deficient strains of S. typhimurium, number of BaP or CP-induced micronuclear
in PCEs in bone-marrow of mice was reduced significantly by the carotenoids
viz., lycopene, canthxanthin, lutein and β-cryptoxanthin (Rauscher
et al., 1998).
Antimutagenicity of carotenoids extracted from five different types of green
peppers (Capsicum sp.) has been reported on S. typhimurium tester
strain YG1024, against the mutagenicity of some nitroarenes (Gonzalez
et al., 1998). Antimutagenic activity of β-carotenre, canthaxanthin,
β-carotene-8-apo-β-carotenal and 8-apo-β-carotene methyl ester
showed a dose dependent decrease in the mutagenicity compared with 1-methyl-3-nitro-1-nitrosoguanidine
and benzo[α]pyrene in S. typhimuium tester strain (Salvadori
et al., 1994).
Diterpenoids: Diterpenoid like erythroxydiol isolated from Aquillaria
agallocha demonstrated antimutagenic as well as antitumor activity (Connolly
et al., 1965). Four novel dibenzoate diterpenes, pulcherrimins A,
B, C and D obtained from roots of Caesalpinia pulcherrima, were found
to be active in DNA repair-deficient yeast mutant (Patil
et al., 1997).
Coumarins: Coumarins are chemically 2H-1-benzopyran-2-ones, widely distributed
in the plant kingdom. A wide range of structures with varying complexity occurs
in angiosperms. Coumarins have been shown to behave both as antimutagenic as
well as anticarcinogen. For instance, coumarin, umbelliferone, 8-methoxypsoralen
isolated from different plant sources have been found to be antimutagenic (Shankel
et al., 2000). Psoralen from Psoralea corylifolia and imperatorin
and osthol from Selinum monniere have been described to inhibit mutagenicity
induced by benzo[α]pyrene. Wall et al. (1988)
observed non-toxicity and high activity of several coumarins including psoralen
from Selinum monniere in the inhibition of mutagenicity of benzo[α]pyrene.
Tannins: Several tannins have been found to reduce the mutagenic activity
of a number of mutagens. Their anticarcinogenic and antimutagenic potential
has been related to their antioxidative property, which is important in protecting
cellular oxidative damage including lipid peroxidation (Chung
et al., 1998). The anticarcinogenic effect of tannic acid was studied
in vivo using micronucleus test and it was found that the frequency of
micronuclei induced by mitomycin C, ethyl nitrosourea or 4-nitroquinoline-1-oxide
in mouse bone marrow cell was decreased by the oral administration of tannic
acid 6 h before the mutagen injection, they also observed the antimutagenic
effect of tannic acid in vivo in the mouse spot test using male PW and
female C57BL/10 mice (Sasaki et al., 1990). Antimutagenic
effects of (+) catechin, ellagic acid and gallic acid against mutagenicity induced
by known mutagens were also reported (Toering et al.,
Hormonal steroids: Some hormonal steroids have been reported to provide
protection against mutagenic effects. Among the steroid molecules bile acids
were shown to have antimutagenic activity towards various direct and indirect
acting mutagens in the Ames test. Ethinyl oestradiol and mestranol both of which
are synthetic derivatives of β-oestradiol largely used in contraceptive
pills these were also strong inhibitors of the mutagenicity acting at nanomolar
concentrations (Wilpart et al., 1986). In experiments
using yeast without an external metabolic activation system the hormones testosterone,
β-oestradiol and dicthyl stilbesterol were antimutagenic and co-recombinogenic
Saponins: As many as thirteen saponins have been isalated from and identified
in Calendula officinalis, C. arvensis, Hedera helix. Four
from C. arvensis and three from H. helix showed antimutagenic
activity against benzo[α]pyrene and a mutagenic concentrate from a smoker
with a dose response relationship in modified liquid incubation technique of
the Salmonella assay (Elias et al., 1990). Ginseng
saponin metabolites introduced by human intestinal bacteria were found antigenotoxic
against benzo[α]pyrene induced clastogenecity (Lee
et al., 1998).
Marine products: Certain secondary metabolites found in marine organisms
have the capability for inhibiting the mutagenicity towards S. typhimurium
of a number of mutagens. Elatol and obtusol are the antimutagenic compounds
isolated from extract of marine animals known as sea hare. These are halogenated
compounds containing bromine and chlorine (Shankel et
al., 2000). Several halogenated active compounds were also found in
red and brown algae. Cymobarbatol and 4-isocymobarbatol were isolated from Cymopolia
barbata, a green algae guided by antimutagenicity assay (Wall
et al., 1989).
Miscellaneous compounds: Ajoene and one of the derivatives of allicin
are the organosulphur compounds found in garlic extract with significant antimutagenic
activity (Ishikawa et al., 1996). Alkaloids and
triterpenpoids were also reported to possess protective actions (Haldar
et al., 2010a). Various other miscellaneous groups of phytocompounds,
such as caffeine, trigonelline and piperine, have been demonstrated to possess
antimutagenic properties (Waters et al., 1996).
Xanthones such as euxanthone and 1,5-dihydroxy-8-methoxyxanthone isolated from
Visma amazonica display considerable antimutagenic activity against 2-aminoanthracene
and EMS (Monache et al., 1983). Haldar
et al. (2010b) reported preventive effects of Indigofera aspalathoides
extract against 20-methylcholanthrene-induced carcinogenesis in Swiss mice.
An 80% ethanol extract of lemon grass (Cymbopogon citrates) was found
to be antimutagenic to various known mutagens in Salmonella mutation assay (Vinitketumnuen
et al., 1994). This extract was shown to inhibit on the formation of
azoxymethane induced DNA adducts and aberrant crypt foci in the rat colon (Suaeyun
et al., 1997). Essential oil from lemon grass (Cymbopogon citrates)
that is used as a constituent of Lemongrass Tea in central and Southern parts
of India was found to possess antimutagenic activity against lead nitrate and
cyclophosphamide induced micronuclei and chromosomal aberration in vivo
in Swiss albino mice (unpublished observation by the author and co-workers).
Its chief constituent citral, a monoterpenoid was reported to possess anticlastogenic
activity (Rabbani et al., 2005).
Numerous references of antimutagenic activities of various plants and their constituents are found in the literature and newer reports of pharmacological screening continually appear in the scientific literature.
FOOD PRODUCTS AS ANTIMUTAGENS
Dietary components exhibit a wide range of activities that can affect mutagenesis.
Naturally occurring substances in foods have been shown in laboratory experiments
to serve as dietary antimutagens. Dietary desmutagens may also act later in
the carcinogenesis process as tumor growth suppressors. Extensive works were
carried out demonstrating the antimutagenic and anticarcinogenic potential of
some commonly consumed spices and vegetables such as turmeric, mustard, green
leafy and allium species of vegetables (Ferguson, 1994).
A human intervention study with vegetable products containing different carotenoids
showed that the supplementation of diet with tomato, carrot or spinach products
resulted in significant decrease in lyphocyte DNA damage (De
The antimutagenic properties of two dietary supplements garlic and mustard
oil were observed against the clastogenic activity of sodium arsenite (Choudhury
et al., 1997). Garlic extract was found to inhibit the mutagenicity
produced by direct acting mutagens such as N-methyl-N'-nitro-N-nitrosoguanidine
and sodium azide using S. typhimuium strains TA100 and TA1535. This antimutagenic
effect of garlic has been attributed to its organosulphur constituents as stated
above (Ishikawa et al., 1996). Casein showed
a strong antimutagenic activity in vivo and ex vivo in the DNA
repair host mediated assay and liquid suspension assay, respectively (Van
Boekel et al., 1997). Yogurt (a fermented milk product) was reported
to be antimutagenic (Bakalinsky et al., 1996).
Antimutagenic effects of guava (Psidium guajava) was reported by Grover
and Bala (1993). The mechanism of antimutagenic effects of mushrooms was
found to be by direct chemical interaction with the mutagens viz. aflatoxin
B1, benzo[α]pyrene and acridine or inhibition of the activation
process in the case of promutagens (Gruter et al.,
1990). Asafoetida and turmeric extracts were found to inhibit microsomal
activation dependent mutagenicity of 2-acetamido fluorine; similar results were
also obtained using Indian spinach leaf extract, curcumin and eugenol which
are phenolics present in turmeric and clove, respectively (Soudamini
et al., 1995). Alkyl-resorcinols, amphiphillic compounds commonly
found in cereal grains demonstrated antimutagenicity in Ames test (Jain
et al., 1987).
OTHER HEALTH BENEFITS BY NATURAL ANTIMUTAGENS
Most of the natural antimutagens exert, apart from their antimutagenic and
anticarcinogenic properties, additional health beneficial effects such as immunomodulator,
hepatoprotective, antihyperglycemic, antihyperlipidemic, cardioprotective, anti-inflammatory
and antirheumatic actions owing to their excellent antioxidant and detoxifying
properties (Shankel et al., 2000). Some other
encouraging observations have been made by some workers during their studies
on natural antimutagens. The effects of known antimutagens, namely polyamines
and related compounds were studied on the development of drug resistance in
a variety of strains and it was found that polyamines produce strong antimutagenic
effects against EMS and MMS-induced antibiotic resistance (Pillai
and Shankal, 1998). It was proposed that natural antimutagenic agents may
prolong the efficacy of human immunodeficiency (HIV) virus therapy which is
otherwise affected by the tendency of transfected human immunodeficiency virus
therapy to mutate to drug resistant forms. Hence, safe intakes of fruits, green
tea polyphenols and cruciferous vegetable were expected to prolong the efficacy
of drug therapy in subjects infected with the human immunodeficiency virus (McCarty,
Untoward mutations are associated with a number of serious diseases for which useful medication are few and treatment is often limited to deal with symptomatologies, many of the environmental pollutants, residues of pesticides and toxins present in food and drugs are common agents of mutagenic damage in human population. Hence there is a need to find natural antimutagenic agents having the potential to prevent or at least delay the onset and severity of genetic damage, which can be incorporated into the regular diet of an individual. Potentially antimutagenic plants include a number of common or ethnic group restricted edible plants, including cereals, pulses, vegetables and spices and medicinal herbs and health tonic plants. Consumption of dietary green leafy vegetable, fruits, carrots, nuts, beverages and green tea etc. can impart necessary protection against the genotoxic effects of mutagens present in food, drugs, cosmetics, industrial waste etc. and thereby help in prevention of cancer and other degenerative disease like atherosclerosis, diabetes mellitus, ischaemic heart disease, rheumatoid arthritis, neurological disorders etc. The search for non-toxic and broad-spectrum natural antimutagens should be extended through systematic screening of the unexplored rich diversity of plant kingdom.
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