Medicinal plants with anti-mutagenic potential

Abstract

This review presents an overview of published studies for a better understanding of the anti-mutagenic potential of medicinal plants and the precise indications for the utilization of natural compounds as chemo-preventive agents. Reports on the anti-mutagenic potential of medicinal plants published from 1997 to 2019 were searched through different scientific databases using the following keywords: medicinal plants and mutagens, carcinogens, the anti-mutagenic potential of medicinal plants. The data relevant to the anti-mutagenic potential of some common medicinal plants is summarized in this mini-review. These medicinal plants include Carum carvi, Withania somnifera, Panax ginseng, Mentha spicata, Curcuma zedoaria, Cassia angustifolia, Cymbopogon citrates, Ipomoea batatas, Glycyrrhiza glabra, Citrullus colocynthis, Capsicum annuum and Asparagus racemosus. An overview of the identified molecules or enzymes being targeted is also presented, with a focus on anti-carcinogenic and/or anti-mutagenic activity. The recent advancements in the research on medicinal plants pave the way for the better understanding and future prospects of the use of natural components as chemo-preventive and chemotherapeutic agents.

Keywords:

• anti-mutagenic activity
• caraway
• ginseng
• mint
• Withania somnifera

Introduction

Indigenous medicinal plants for the treatment of different diseases are receiving increasing attention. European countries, as well as Arabian countries, are taking a revived interest in herbal medicines due to their efficacy, safety and cost-effectiveness [1]. Plants have been used for alleviating the sufferings from various kinds of conditions [2, 3]. The interest in the study of such medicinal plants has developed with the aim to obtain therapeutically effective drugs [4]. Many clinically documented herbal medicines have appeared in the official and unofficial compendia [5, 6]. Many modern medicines have been developed because of research on plant extracts, including atropine, reserpine, ergot and digitalis, which are continuously used in modern medicines. Traditional western medicines have not been able to completely satisfy the population all over the world, so most of the population is returning to complementary and alternative medicines, which explains the greater acceptability of herbal medicines [7, 8]. Medicinal plants have been used for the treatment of various diseases and their activities have been reported. Anti-mutagenic activities of extracts of various medicinal plants have been evaluated by using the microsomal system/Salmonella to investigate whether they contain direct or indirect anti-mutagens. Many plant extracts show anti-mutagenic activity, including Pteris multifida, Smilax china and Prunella vulgaris [9–11]. For example, Sukumaran et al. [12] reported the inhibition of tobacco-induced mutagenesis by eugenol and plant extracts. The anti-mutagenicity of turmeric oil has been reported [13]. For many years it has been a continuous struggle to find natural substances having the ability to inhibit or reverse multi-stage carcinogenesis [14]. A wide range of constituents present in medicinal plants or dietary herbs has been reported for their potential to inhibit carcinogenicity [15]. Various dietary compounds or herbs have demonstrated inhibitory activities on the progression of cancer, and most often, their chemo-preventive effects are linked to anti-inflammatory or anti-oxidant activities that some of their components possess [16–18]. Frequent consumption of vegetables, spices and fruit is linked to lower risks of different cancers as reported by epidemiological studies [19, 20]. This protective activity is often attributed to the steroids and flavonoids that are found in medicinal plants and are a fundamental ingredient of human nutrition [21, 22]. This review highlights some common medicinal plants possessing anti-mutagenic activities.

Methodology

For this literature review, published articles were searched through different databases, including PubMed, Medline, Scopus, Science Direct, Google Scholar and Web of Science. The literature search was performed using the following keywords: medicinal plants and mutagens, carcinogens, the anti-mutagenic potential of medicinal plants; and the relevant articles published in 1997–2019 were downloaded. The reported data on the anti-mutagenic role of studied medicinal plants were summarized to provide a brief overview of medicinal plants with potential therapeutic role against mutagens/carcinogens.

Molecular mechanisms underlying the anti-mutagenicity of natural products

The following mechanistic pathways of anti-mutagenicity have been proposed and reviewed [23]:

1. Inactivation of mutagens directly.

2. Inhibition of chemical or metabolic activation of mutagens.

3. DNA protection against the action of mutagens.

4. Modification in DNA repair and DNA replication.

5. Hepatic detoxification system modulation.

For example, Teel [24] and Ahmed et al. [25] described a mechanism of anti-mutagenesis by ellagic acid via making adducts with DNA and thus masking the binding sites to be occupied by the carcinogens or mutagens.

Plants having anti-mutagenic activity

The results from the performed literature search showed an array of plant extracts with anti-mutagenic properties (Table 1). In this mini-review, we discuss some of the medicinal plants with reported anti-mutagenic potential. These plants include Carum carvi, Withania somnifera, Panax ginseng, Mentha spicata, Curcuma zedoaria, Cassia angustifolia, Cymbopogon citrates, Ipomoea batatas, Glycyrrhiza glabra, Citrullus colocynthis, Capsicum annuum and Asparagus racemosus. Further, we summarized the molecules or enzymes being targeted and consequently results in anti-carcinogenic and/or anti-mutagenic activity. The plants that have potential against carcinogenesis and mutagenesis are also highlighted.

Table 1. Other medicinal plants possessing anti-mutagenic activity.

Plant	Family	Part used	Active constituents	References
Pueraria lobata	Leguminosae	Roots	Isoflavone	[26]
Syzygium aromaticum	Myrtaceae	Buds	Phenylpropanoids	[27]
Aronia melanocarpa	Rosaceae	Fruits	Anthocyanins	[28]
Kalopanax pictus	Araliaceae	Stem bark	Hederagenin monodesmosides and bisdesmosides	[29]
Pistacia lentiscus	Anacardiaceae	Leaves	Pentagalloylglucose and Gallic acid	[30]
Liquidambar orientalis Mill	Hamamelidaceae	Leaves	Phenolic compounds	[31]
Aspalathus linearis	Fabaceae	Leaves	Flavonoids	[32]
Calendula officinalis	Asteraceae	Aerial parts	Saponins	[33,34]
Carum copticum	Apiaceae	Fruit	Phenolic terpenoids	[35]
Lupinus campestris	Fabaceae	Seeds	Phenolic compounds, oligosaccharides and quinolizidinic alkaloids	[36]
Gleditsia sinensis	Leguminosae	Thorns	Triterpenoid, steroids, stigmasterol and beta sitositosterol	[37]
Scutellaria baicalensis Georgi	Lamiaceae	Roots	Flavones	[38]
Ginkgo biloba	Ginkgoaceae	Leaves	Polyphenols	[39]
Belamcanda chinensis	Iridaceae	Rhizomes	Iridin and tectoridin in the glycoside fractions and the 5,6,7,3′-tetrahydroxy-4′-methoxy isoflavone and irigenin, tectorigenin	[40]
Hamamelis virginiana	Hamamelidaceae	Bark	Proanthocyanidins	[41]
Cassia tora	Caesalpinaceae	Seeds	Anthraquinone aglycones and naphthopyrone glycosides	[42]
Salvia officinalis	Lamiaceae	leaves	Essential oil and its monoterpenes	[43]
Pistacia lentiscus	Anacardiaceae	Leaves	Pentagalloylglucose	[44]
Psychotria umbellata Vell	Rubiaceae	Leaves	Monoterpene indole alkaloid psychollatine	[45]
Caralluma adscendens Roxb	Asclepiadaceae	Flowers	Pregnane glycosides	[46]

Carum carvi L

Carum carvi (caraway) belongs to family Apiaceae. Its seeds are widely used for medicinal purposes and they contain fatty acids and volatile oils [47, 48]. The seeds of caraway are commonly used in cookies and loaves of bread as a seasoning [49]. The data reported in earlier studies suggested that the use of spices reduced the risk of gastric cancer [50, 51]. It was found that hot water extracts of C. carvi are anti-mutagenic against ICR-170, nitroso-dimethylamine and MNNG (N-methyl-N’-nitro-N-nitrosoguanidine) [52]. D-Carvone, the main constituent of caraway oil, exhibited the potential to inhibit the development of stomach and pulmonary tumours induced by diethylnitrosamine [53–57]. Mazaki et al. [58] reported the inhibitory activities of C. carvi and its component on MNNG-induced mutagenicity and it was suggested that O₆ methylguanine DNA methyltransferase may be responsible for the anti-mutagenic effect of Carum carvi. Using sequential extraction of caraway seeds with methanol, n-hexane and boiling water, it was reported that hot water extracts have more enhanced anti-mutagenic potential [59].

Withania somnifera

Withania somnifera (family Solanaceae) is a well-known medicinal plant widely found in India and the Mediterranean region [60, 61]. The parts used are the roots, bark, seeds, flowers, stem and leaves. It contains withaferin and is used as an inhibitor of human osteosarcoma, breast, colon, central nervous system (CNS), lung, bladder cell lines, and cancer [62]. Withaferin-A is a purified steroidal lactone from the leaves of W. somnifera [7] and has much bioactive potential, including anti-inflammatory, pro-apoptotic [63] and anti-proliferative effects [64]. Another study [65] reported that combined treatment of withaferin-A with hyperthermia-induced significant apoptosis in HeLa cells by increasing the oxidative stress and reducing the GSH/GSSG ratio, JNK activation and mitochondria-caspase dependent apoptotic pathway involvement. Withaferin-A has been reported as a potential anticancer compound, as it inhibits tumour growth, metastasis and angiogenesis. More recently, it was evaluated that withaferin-A exhibited synergistic effects of chemotherapeutic agents like doxorubicin and cisplatin and induced cell death by reactive oxygen species generation leading to DNA damage resulting in apoptosis [66, 67].

Khanam and Devi [68] investigated methanolic extracts of W. somnifera roots for protective effect on mitomycin induced damage to the bone marrow and the anti-oxidant enzymes in the liver of mice. The protective effect was assessed using mouse bone marrow micronucleus test against micronuclei (MN) formation in normochromatic cells (NCEs) and polychromatic cells (PCEs) induced by 4 mg/kg b.w., i.p Mitomycin C. The study findings suggested that W. somnifera extract is useful for the prevention of DNA damage and one of the action mechanisms might involve scavenging the active oxygen radicals induced by the mutagens [68].

Panax ginseng

Panax ginseng belongs to family Araliaceae; its roots are utilized as a general stimulant in traditional Oriental medicine for enhancing longevity, health and vitality, especially in the elderly [69]. Its chemical constituents are theophylline, saponins, ginsenosides, caffeine, xanthines and theobromine [70]. It has tonic, adaptogenic and anti-cancer activity [71–73]. Rhee et al. [74] reported the anti-mutagenic effect and transformation by P. ginseng root extracts. Raghavendran et al. [75] observed that P. ginseng amends cytokines in bone marrow toxicity and myelopoiesis: ginsenoside Rg1 moderately supports myelopoiesis. White ginseng can reduce the mitotic division of cells, and prevent the metastasis of melanoma (B16) [76]. It is reported to enhance the endogenous anti-oxidant system, which suppresses the production of harmful free radicals [77]. Interestingly, the Korean red ginseng is chemically processed in such a way that its chemical composition is transformed and its biological properties are altered according to the need [78]. Ginseng alkaloids and saponins prevent the metastasis and growth of lung cancer by preventing the encroachment and bonding of tumour cells with each other and with the neighbour cells [79, 80]. Red ginseng is capable of preventing the metastasis of a tumour by restricting the activities of tumour cells and increasing their lysosomal vulnerability [81, 82]. The extract of P. ginseng, when given orally to mice, showed a significant reduction in the number of tumour cells, shrinkage of tumour cells, and also increased the time duration of the appearance of tumour cells [83]. Alpha-pyrrolidone, an alkaloid of ginseng, was tested for the first time in 1960 and was shown to have inhibitory effects on tumour cell lines [84–89].

Mentha spicata

Mentha spicata belongs to the Lamiaceaefamily. The parts used are its bark and fruit. It contains nodifloretin, chrysoberyl, protocatechuic acid and protocatechuic aldehyde [90, 91]. It has antimicrobial [92] and anti-oxidant potential [93]. Yu et al. [94] reported the anti-mutagenic activity of M. spicata and evaluated its considerable inhibitory effects against mutagens. Some early studies reported its anti-mutagenic activities [90, 95–99]. The volatile ingredients of spearmint like limonene, terpenoids, menthone, carvone, dihydrocarvinone, menthol and other compounds belonging to the same class have therapeutic and cancer chemo-preventive activities [100]. Aqueous extract of M. spicata acted as an inhibiting agent or anti-mutagen via inhibitory activities on DNA adduct formation or carcinogen metabolism in vitro [101].

Curcuma zedoaria

It belongs to family Zingiberaceae. Its common name is Narkachur/White turmeric and is found in India and Indonesia. It contains curcumenol, procurcumenol, zederone and comosone II [102, 103]. The parts used are the leaves. It has anti-oxidant [103] and anti-cancer activity [104]. Curcumin has been reported as an anti-mutagenic agent [105]. In another study, two extracts of C. zedoaria (aqueous and methanol) exhibited no mutagenicity when investigated in several Salmonella typhimurium strains with or without the S9 mix [106]. Furthermore, the methanolic extract exhibited better anti-mutagenic activity than the aqueous extract against 2-amino-3-methylimidazo (4,5-f) quinoline and 4-nitroquinoline-N-oxide. The inhibitory activities of the two extracts on lipid peroxidation were comparable [107]. Extracts of C. zedoaria had a moderate anti-mutagenic effect against mutation induced by benzo [a] pyrene [9–11].

Cassia angustifolia

It belongs to family Poaceae. Its common name is senna and is found in Sri Lanka. It contains flavonoids, apigenin, phenolic compounds, luteolin, kaempferol and quercetin [108]. The parts used are its leaves [109]. It has anti-mutagenic activity [110]. Senna is widely used as a laxative [111], however, potential side effects like genotoxicity have also been reported [112]. Its water extract showed anti-mutagenic activity by four experimental assays. Furthermore, the aqueous extract was not mutagenic or cytotoxic to Escherichia coli strains [113].

Cymbopogon citratus

It belongs to family Leguminosae. Its common name is lemongrass and is found in India. It contains tinnevellin glycoside, D-3-O-methyl inositol and kaempferol [114]. The parts used are its leaves. It has anti-cancer activity [115]. The alcoholic extract of Lemongrass is reportedly anti-mutagenic [116, 117].

Ipomoea batatas L

Ipomoea batatas L. (common name sweet potato) belongs to family Convolvulaceae. It is found in America and contains phenolic acid, tannins, saponins, coumarin, anthraquinone and triterpenes [118, 119]. The parts commonly used are the roots. Yoshimoto et al. [120] demonstrated that I. batatas possess anti-mutagenic effect due to its mono-, di-, and tri-caffeoylquinic acid derivatives. The aqueous extracts of I. batatas had anti-mutagenic activities against Trp-P-1 in Salmonella typhimurium TA 98. Among four varieties of different root flesh colours, the Ayamurasaki variety (purple colored flesh) significantly decreased the mutation rate induced by tryptophan pyrolysis products and by the grilled meat of beef (dimethyl sulfoxide extract), and it was hypothesized that like-wise the heterocyclic amines, the pigment in anthocyanin reduced the mutation activities [121]. Two pigments of anthocyanin obtained from the purple-coloured variety of I. batatas effectively inhibited the potential of tryptophan pyrolysis products to induce mutations in rat liver homogenate [122].

Glycyrrhiza glabra L

It belongs to family Leguminosae. Its common name is liquorice and is found in Southern Europe and different parts of Asia, including India. It contains glycyrrhizic acid, glycyrrhizin and Licor-phenone [123]. The parts used are its rhizome [124]. It has anti-mutagenic activity. Certain phytoconstituents can be employed as dietary supplements, functional foods and even as drugs due to their chemo-preventive effects [125]. The natural compounds may serve as potential chemo-preventive agents due to their anti-genotoxic and free-radical scavenging activity [126]. Moreover, they act to prevent the modulatory functions of some mutagenic agents in the cytoplasmic environment of Salmonella typhimurium and play a significant role to restrict the microbial infection [127]. Extracts of G. glabra were fractionated and isolated to show that its biochemical compounds are effective against the mutagenicity caused by oxidative stress [128, 129]. Methanolic extracts of G. glabra are effective in preventing the mutations caused by oxidative mutagens; especially glycyrrhizic acid was more effective in reducing the genotoxicity of the oxidative mutagens [130]. Glycyrrhizic acid (120 μmol/L) shows high potential to reduce free radicals in the DPPH radical scavenging assay, suggesting that it potentially modulates the activities of genotoxins via free-radical scavenging [130]. In addition, Karahan et al. [131] confirmed the anti-oxidant potential of the methanolic extracts of G. glabra var. glandulifera roots and reported the antimicrobial activities that were less potent against gram-negative than against gram-positive ones. Their study results indicated that the biological activities and the contents of chemical compounds in the natural liquorice populations might be affected under different environmental conditions in each habitat [131].

Citrullus colocynthis

It belongs to family Cucurbitaceae. Its common name is bitter apple [132] and is found in Africa and India. It contains isoorientin 3′-Ο-methyl ether, isovitexin and iso-saponarin [14]. The parts used are mainly their seeds. It has anti-cancer activity [133]. In vitro analysis of the methanolic extracts of the seeds of C. colocynthis was carried out in the bacterial system to observe its effects on mutagenesis. The methanolic extract of seeds of C. colocynthis was not effective in inducing resistance to serve as a mutagen for the antibiotic treatments (streptomycin & rifampicin). Therefore, these findings suggested that plant extract had no genotoxic effects on the cell’s system [134, 135]. C. colocynthis fruit extract mitigated the genotoxic potential of cyclophosphamide in mice bone marrow cells [134, 135].

Capsicum annuum

It belongs to the family Solanaceae. Its common name is pepper and is found in the Americas and South Asia. Although it is not native to Europe, it is grown there too. It contains capsaicin [136]. The parts used are fruits. It has anti-mutagenic activity [137]. Capsaicin (CPS) is the principal constituent of peppers [138] and shows antitumor activity by targeting several molecular pathways [139].

Asparagus racemosus

Asparagus racemosus (family Liliaceae) is an important medicinal plant shown to increase cellular vitality and resistance and promote the general wellbeing. It is widely distributed in India, the Southern part of China, Sri Lanka, Australia, Java and tropical Africa. The pharmacological activities of this plant include its use as a brain tonic, antiepileptic, antihypertensive agent, a regulator of cardiac disorders, in the treatment of spermatogenic irregularities, oligospermia and male genital dysfunction [140–142]. Methanolic and aqueous-methanolic extracts of A. racemosus roots have shown anti-mutagenic effect against sodium azide and 4-nitro-ophenylenediamine (NPD) induced mutations through the Ames mutagenicity assay using Salmonella typhimurium strains TA98 and TA100 [143]. Hence, A. racemosus extracts have been indicated as a new source of anti-mutagenic agents [143].

Conclusions

This mini-review briefly documents some reports on the anti-mutagenic potential of different medicinal plants and alternative components in prokaryotic and eukaryotic model systems. The large body of evidence demonstrating the anti-mutagenic activities of different plant extracts has raised hopes that they may also have chemo-preventive and therapeutic potential in different cancer models. Proofs from both in vitro and in vivo studies advocate that they can definitely restrain multiple molecular targets that play a significant role in both chronic inflammation and cancer, but in some cases, there may be a difference in efficacy due to the dosage, the origin of the extract or the cell line used. However, in future, more targeted investigations are needed for better understanding of the molecular mechanisms of action against different mutagens. Further, clinical studies, as well as more research efforts targeting appropriate drug delivery systems are necessary to exploit completely their reported efficacy for the prevention and management of various cancers. Finally, clinical studies in humans could considerably improve our understanding of the macroscopic activities of the active compounds in these common medicinal plants.

Author contributions

MA, MR, RZ and MD conceived the review, drafted the manuscript, analyzed the literature and critically reviewed the manuscript. AWC, AH and MM performed the literature search and took part in analyzing the literature. SAZ, MAS and FSK involved in literature search and critically read the manuscript. All the authors approved the final draft for publication.

Disclosure statement

No potential conflict of interest was reported by the authors.