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Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)
REVIEW ARTICLE
Are Genotoxic and Carcinogenic Compounds Present in
Malaysian Traditional Medicines and Herbal Supplements? A
Review Based on the Malaysian Herbal Monograph
Nur Azra. M. Pauzi1,2, Manraj S Cheema3, Amin Ismail4, Ahmad Rohi Ghazali5, Rozaini Abdullah1,6
1
Department of Environmental and Occupational Health, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia,
43400 Serdang, Selangor, Malaysia
2
Ministry of Health, Kompleks E, Pusat Pentadbiran Kerajaan Persekutuan, 62590 Putrajaya
3
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang,
Selangor, Malaysia
4
Department of Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor,
Malaysia
5
Department of Biomedical Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, 50300 Kuala Lumpur,
Malaysia
6
Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang,
Selangor, Malaysia
ABSTRACT
The use of medicinal plants is significant in the long tradition of folklore and traditional medicine in Malaysia, which
continues to the present day. To support the growth of the local herbal industry, the Malaysian Herbal Monograph
(MHM) was introduced, with monographs of 76 commonly used local medicinal plants published to date. Despite
their health benefits and important pharmacological activities, 11 plant species that could potentially contain geno-
toxic and carcinogenic phytochemicals such as alkenylbenzenes (methyleugenol, safrole and estragole) and pyr-
rolizidine alkaloids (monocrotaline, lasiocarpine, riddelliine and senecionine) were investigated. A further search on
QUEST3+, a database maintained by the National Pharmaceutical Regulatory Agency, Ministry of Health
Malaysia, revealed that hundreds of registered natural products, including traditional medicines and herbal supple-
ments (TMHS), contain these plant species as ingredients. In conclusion, consumers could be exposed to genotoxic
and carcinogenic phytochemicals through consumption of these registered TMHS thus increasing the risk of devel-
oping cancer.
Keywords: Genotoxic, Carcinogenic, Traditional medicine, Herbal supplements, Malaysian Herbal Monograph
Corresponding Author: of primary health care, and 80% of the world’s population,
Rozaini Abdullah, PhD especially in Africa, Asia, and Latin America still rely
Email: rozainiabdullah@upm.edu.my on plants-based medicines for primary care (1-4). The
Tel: +603 8609 2975 use of traditional and complementary medicine is also
widespread in Malaysia. It is estimated that 30% of the
INTRODUCTION Malaysian population have used traditional medicine
to prevent or treat diseases (5). The increasing use of
The use of plants or herbs for medicinal purposes and traditional medicine and herbal supplements (TMHS)
health maintenance has been documented since ancient has led to a global expansion of the herbal industry;
civilization and continues in the modern society, with in 2008, the value of herbal medicines worldwide was
approximately 25% of medicines prescribed worldwide approximately USD 60 billion (6), in 2016, consumers
(1) and more than 50% of medicines used in clinical spent approximately USD 7.452 billion on plant food
settings are derived from natural resources (2). In supplements and the global market for botanical and
addition, the World Health Organization (WHO) has plant-derived drugs is expected to grow to USD 39.6
recognized herbal medicines as an essential component billion by 2022 (7).
Mal J Med Health Sci 17(SUPP8): 207-222, Oct 2021 207Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)
Meanwhile in Malaysia, the value of the herbal industry evaluated for their toxicological and safety profile before
is also growing at a rate of 8 to 15 percent per year being released for sale (13, 14). Furthermore, most
and is expected to be worth MYR 32 billion in 2020 regulatory authorities do not take adequate measures to
(8). Due to the high demand for TMHS from local and ensure the safety and quality of herbal medicines. The
international markets, combined with Malaysia’s great requirements for non-clinical and clinical studies for
biodiversity, the herbal industry has always been one herbal medicines are also less stringent. In Europe, the
of the most substantial economic drivers that could safety status of herbal medicines is based on the absence
contribute to the nation’s economic growth (9). In 2011, of known adverse reactions for established long-standing
the Malaysian government identified the herbal sector traditional use. In the United States of America, herbal
as an emerging source for Malaysia’s economic growth and dietary supplements are less regulated by the Food
under the National Key Economic Area (NKEA). One of and Drug Administration (FDA), as they are deemed to be
the projects under this programme is the development of of low hazard risk (12, 15). In Malaysia, toxicity studies
the Malaysian Herbal Monograph (MHM), an invaluable are only required for products that contain a new plant
reference source comprising scientific monographs ingredient, or a new combination of plant ingredients,
of Malaysian herbs and medicinal plants (10). Under but not for those plants that have been used in the past
the initiative, 76 monographs have been published, as without causing safety concerns (16). Without a proper
presented in Table I. policy and regulatory system, unregistered and poor-
quality TMHS can be easily sold in the market, exposing
The lack of evidence on the toxic effects of herbal consumers to the harmful compounds, thus leading to
medicines has raised concerns over their safety, serious adverse effects on their health.
especially when taken excessively or chronically and
when taken concomitantly with other medicines (3, 11). To the best of our knowledge, the present paper is the
Many studies have shown that herbal medicines can first review that attempts to identify the presence of
induce carcinogenicity, teratogenicity, hepatotoxicity, genotoxic and carcinogenic phytochemicals in the 76
nephrotoxicity, and others (3, 11, 12). Unlike modern medicinal plant species published under the MHM.
pharmaceuticals, most TMHS have never been
Table I: 76 medicinal plants species published under the Malaysian Herbal Monograph initiative
Binomial nomenclature Local name Family Plant part(s)
Acalypha indica L. Kucing galak Euphorbiaceae Aerial
Alpinia galanga (L.) Willd. Lengkuas Zingiberaceae Rhizome
Andrographis paniculate (Burm.f.) Wall. ex
Hempedu bumi Acanthaceae Herb
Nees
Annona muricata L. Durian belanda Annonaceae Leaf
Aquilaria malaccensis Lamk Karas Thymelaeceae Leaf
Areca catechu (L.) Pinang Arecaceae Seed
Averrhoa bilimbi Linn Belimbing buluh Oxidaceae Fruit
Baeckea frutescens L. Cucur atap Myrtaceae Leaf
Blumea balsamifera (Linn.) DC Capa Asteraceae Leaf
Brucea javanica (L.) Merr. Melada pahit Simaroubaceae Fruit
Cananga odorata (Lam.) Hook. F. & Thomson Kenanga Annonaceae Flower
Carica papaya L. Betik Caricaceae Leaf
Centella asiatica (L.) Urb. Pegaga Umbelliferae Herb
Chromolaena odorata (L.) R. M. King & H.
Pokok kapal terbang Asteraceae Leaf
Robinson
Cinnamomum verum J. S. Pres; Kayu manis Lauraceae Leaf and stem bark
Citrus hystrix D. C. Limau purut Rutaceae Fruit and leaf
Clinacanthus nutans Lindau Belalai gajah Acanthaceae Leaf
Cosmos caudatus Kunth Ulam raja Asteraceae Leaf
Curcuma aeruginosa Roxb. Temu hitam Zingiberaceae Rhizome
Curcuma longa L. Kunyit Zingiberaceae Rhizome
Curcuma zedoaria (Christm.) Roscoe Temu kuning Zingiberaceae Rhizome
Cymbopogon citratus (DC.) Stapf Serai makan Poaceae Leaf-sheath and stem
Eclipta prostrata (L.) L. Urang aring Asteraceae Leaf
Elaeis guineensis Jacq. Kelapa sawit Palmae Leaf
CONTINUE
208 Mal J Med Health Sci 17(SUPP8): 207-222, Oct 2021Table I: 76 medicinal plants species published under the Malaysian Herbal Monograph initiative (cont.)
Binomial nomenclature Local name Family Plant part(s)
Elephantopus scaber Linn. Tutup bumi Asteraceae Whole plant
Etlingera elatior (Jack) R.M. Smith Kantan Zingiberaceae Flower
Euphorbia hirta L. Ara tanah Euphorbiaceae Aerial
Eurycoma longifolia Jack Tongkat ali Simaroubaceae Root
Ficus deltoidei var. deltoidei Jack Mas cotek Moraceae Leaf
Garcinia atroviridis Griff. Ex. T. Anderson Asam gelugur Clusiaceae Fruit
Garcinia mangostana Linn Manggis Clusiaceae Rind
Gynura procumbens (Lour.) Merr Sambung nyawa Asteraceae Leaf
Hibiscus sabdariffa L. Roselle Malvaceae Calyx
Kaempferia galanga L. Cekur Zingiberaceae Rhizome
Labisia pumila (Blume) Fern.-Vill var. ala-
Kacip fatimah Primulaceae Root
ta (Scheff.) Mez
Lignosus rhinoceros (Cooke) Ryvarden Kulat susu rimau Polyporaceae Sclerotium
Marantodes pumilum (Blume) Kuntzevar. pum-
Kacip Fatimah variety pumila Primulaceae Leaf and root
ila
Melastoma malabtahricum L. Senduduk Melastomatacea Leaf
Mitragyna speciosa (Korth.) Havil Ketum Rubiaceae Leaf
Momordica charantia L. Peria katak Cucurbitaceae Fruit
Morinda citrifolia L. Mengkudu Rubiaceae Fruit and leaf
Moringa oleifera Lam. Merunggai Moringaceae Leaf
Muraya koeniigi L. Spreng Kari Rutaceae Leaf
Myristica fragrans Houtt Buah pala Myristicaceae Seed and arillus
Ocimum basilicum L. Selasih Lamiaceae Leaf
Orthosiphon aristatus (Blume) Miq Misai kucing Lamiaceae Leaf
Pandanus amaryllifolius Roxb. Pandan wangi Pandanaceae Leaf
Parkia speciose Hassk. Petai Leguminosae Seed
Persicaria minor (Huds.) Opiz Kesum Polygonaceae Leaf and twig
Phaleria macrocarpa (Scheff.) Boerl Mahkota dewa Thymelaeceae Fruit and leaf
Phyllanthus amarus Schumach & Thonn Dukung anak Phyllanthaceae Shoot
Phyllanthus niruri L. Dukung anak Phyllanthaceae Herb
Phyllanthus urinaria L. Dukung anak Phyllanthaceae Shoot
Piper betle L. Sireh Piperaceae Leaf
Piper nigrum L Lada hitam Piperaceae Fruit
Piper sarmentosum Roxb. Kadok Piperaceae Leaf
Senna alata (L) Roxb Gelenggang Fabaceae Leaf
Strobilanthes crispus (L.) Bremek Pecah beling Acanthaceae Leaf
Swietenia macrophylla King Tunjuk langit Meliaceae Seed
Syzygium aromaticum (L.) Merr. & L.M.Perry Cengkih Myrtaceae Flower buds
Syzygium polyanthum (Wight.) Walp Salam Myrtaceae Leaf
Tinospora crispa (L.) Hook.f. & Thomson Patawali Menispermaceae Stem
Vernonia amydalina Delilie Panjang hayat (Bismillah) Asteraceae Leaf
Vitex negundo L. Lemuni Verbenaceae Leaf
Zingiber montanum (J. Koenig) Link ex A. Dietr Bongelai Zingiberaceae Rhizome
Zingiber officinale Roscoe Halia Zingiberaceae Rhizome
Zingiber officinale var. rubrum Theilade Halia bara Zingiberaceae Rhizome and leaf
Zingiber zerumbet (L.) Smith Lempoyang Zingiberaceae Rhizome
Mal J Med Health Sci 17(SUPP8): 207-222, Oct 2021 209Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)
The role and significance of the Malaysian Herbal in the MHM serves as a guideline or benchmark in terms
Monograph of quality control, thus ensuring that only high-quality raw
materials are used. Additionally, the chromatographic
An herbal monograph is “a document that defines a fingerprint or profile included in the monograph further
botanical drug and provides information that allows for improves the standardization of herbal materials and
its proper identification” (17). It provides comprehensive quality evaluation of herbal medicines. In essence, the
information including the nomenclature and synonyms use of the MHM as the main reference for local herbs and
of a plant species, botanical information such as plant medicinal plants can promote the local herbal industry,
morphology and microscopic characteristics, list of especially when exported or marketed internationally.
phytochemical constituents, indications, traditional Unfortunately, despite the advantages, the MHM is still
uses, dosage, and identification and purity tests. not a legally enforceable document in Malaysia.
Therefore, a monograph is usually requested by
the national regulatory authority in the registration Safety concerns of traditional medicines and herbal
procedure to support the use of a plant in an herbal supplements
product formulation. Some monographs also contain
biological and pharmacological information including The notion that herbal medicines are always safe is
pharmacological activities and preclinical safety data, misleading, as many studies have reported side effects
such as the EU Herbal Monograph (18), the WHO caused by commonly used medicinal plants, ranging
Monographs on Selected Medicinal Plants and the from mild to severe acute or spontaneous adverse
MHM. reactions. For example, valerian (Valeriana officinalis),
which is traditionally used to improve sleep causes
The MHM is a continuous effort of seven agencies, extreme fatigue. Black cohosh (Actaea racemosa) used
working collaboratively to develop the key reference to alleviate menopausal symptoms such as hot flashes,
that provides scientific information on commonly causes upper abdominal pain and hepatotoxicity, and
used local herbs. The MHM committee consists of concurrent use of Ginkgo biloba with the anticoagulant
representatives from Malaysian research universities drug warfarin can result in haemorrhage (19). Medicinal
(Universiti Putra Malaysia, Universiti Kebangsaan plants may also contain toxic compounds that occur either
Malaysia and Universiti Sains Malaysia), the National naturally or through environmental and microorganism
Pharmaceutical Regulatory Agency (NPRA), the Institute contamination (20, 21). For instance, chewing of betel
for Medical Research (IMR), the Malaysian Agricultural quid and areca nut, which is an ancient practice in some
Research and Development Institute (MARDI) , the culture in Asia is known to increase the risk of cancer in
Forest Research Institute Malaysia (FRIM) and the Herbal the oral cavity, pharynx and oesophagus (22). Through in
Development Office of Ministry of Agriculture and vivo and in vitro models, several compounds, including
Agro-Based Industry. The MHM also aims to promote arecoline, arecaidine, and nitroso-derivatives formed
local medicinal plants in the global herbal industry and during the act of chewing of betel quid and areca nut,
to support the development of the local herbal industry are suspected to be the major cause of mutagenicity,
as one of the most important economic resources in the genotoxicity and carcinogenicity (23, 24).
country. Like the international monographs, such as the
WHO Monographs on Selected Medicinal Plants, the Toxicity of herbal medicines can also result from
MHM contains extensive scientific information on the misidentification of the correct species, use of incorrect
species of the plants. To date, four MHM books have plant parts, and adulteration with closely related plant
been published – MHM Volume 1, 2 and 3 and the species or with synthetic drugs (1,3). Adulteration of
latest, MHM 2015; all monographs are also available herbal medicines can cause severe adverse reactions
digitally through http://globinmed.com/. Many sectors in consumers, such as agranulocytosis, Cushing’s
can benefit from the information in the MHM including syndrome, hypoglycaemia, intestinal hemorrhage,
regulatory agencies, manufacturers, academia and diabetes, hypertension, and cardiac arrhythmia (25).
researchers, health professionals and even the public From 2003 to 2017, 166 types of adulterants were
too. For example, the evidence-based therapeutic detected in herbal products and medicines in China
uses of herbal medicines and the pharmacological, with the intention of potentiating clinical effects, as
toxicological and safety data facilitate decision making an industrial dye, or to increase the product weight or
by the regulatory agencies for product registration. quantity (26). In addition, chlorpheniramine, piroxicam,
The detailed information on plant morphology and betamethasone, caffeine and oxethazaine were detected
characteristics of the powder, presented in the form in 23 Chinese herbal medicines, with three products
of microscopic images, serves as an excellent guide in exceeding recommended prescription doses (27) and
authentication of the plant species and part(s), ensuring 28 of 40 batches of health foods adulterated with PDE-
that the appropriate starting material enters the final 5 inhibitor (28). The addition of synthetic drugs often
product. The specification for purity and safety tests, involve groups of herbal medicines indicated for weight-
such as tests for ash content, water and ethanol extracts, loss, sexual enhancers, treatment of rheumatic and
moisture content, microbial limits and heavy metal tests inflammatory diseases, diabetes and hypertension (29).
210 Mal J Med Health Sci 17(SUPP8): 207-222, Oct 2021Another concern that contributes to the safety of and unavoidable. For example, phytochemicals such
TMHS is the lack of effective quality control in the raw as aristolochic acid, alkenylbenzene such as safrole,
materials and manufacturing of the products (1). Poor pyrrolizidine alkaloid such as monocrotaline, and others
agricultural practices such as improper use of pesticides as shown in Table II (40, 41);
and cultivation of plants in areas with soil and water II. Naturally occurring but avoidable
contaminated by industrial wastes lead to accumulation compounds, such as the carcinogenic aflatoxin, which
of pesticide residues and heavy metals such as arsenic, is ubiquitous in foods such as grains and nuts, and
mercury, lead, cadmium, manganese, zinc and animal feed. Aflatoxin is a metabolite produced by
chromium (30, 31). Consumption of plants contaminated the fungi Aspergillus flavus, Aspergillus paratictus and
with heavy metals can lead to serious health effects in Aspergillus nomius, (42, 43), and can be minimized by
humans; for example mercury, arsenic, cadmium and good agricultural and storage practices (34, 44);
lead can cause mutagenic effects even at low levels III. Anthropogenic chemicals in food that cannot
(31). In addition, inadequate cleaning and drying, as be avoided, such as 2,3,7,8-tetracholordibenzo-p-
well as improper storage conditions of the herbs, causes dioxin (2, 3, 7, 8–TCDD), a by-product of incomplete
the raw herbal materials to harbour high levels of combustion of fossil fuels and woods. It contaminates the
bacteria and fungi (32). Pathogens such as Salmonella, environment, including air and soil, and accumulates in
Eschericia coli and Pseudomonas aeurignosa in TMHS food (34, 45);
have caused serious health issues worldwide, especially IV. Anthropogenic chemicals deliberately added
among immunocompromised consumers (33). On the to food and are avoidable, such as saccharin, an artificial
other hand, certain strain of fungus such as Aspergillus sweetener, or food dyes (34, 46). Smoking of meat
ochraceus, A. carbonarius, A. niger and Penicillium products, fish and dairy products generates genotoxic
verrucosum produce ochratoxin A which is classified as and carcinogenic polycyclic aromatic hydrocarbons
possibly carcinogenic to human (Group 2B) and has also (PAH) (47).
been associated with Balkan endemic nephropathy (34,
35). In this review, we are focusing on the genotoxic and
carcinogenic phytochemicals that fall into category I
Although regulatory agencies have established including alkenylbenzene, pyrrolizidine alkaloid and
permissible limits for heavy metals and microbial aristolochic acids. Alkenylbenzene (Fig 1a) is a group of
contaminants, there have been reports of the TMHS phytochemical compounds commonly found in herbs
in the market with levels of microbial contaminants and spices (e.g., fennel, tarragon, anise, nutmeg, basil,
and heavy metals exceeding these limits (36-38). The coriander, ginger, and many others), aromatic oils,
scenario demonstrates the lack of thorough regulatory vegetables and fruits (e.g., bananas, grapefruit juice).
measures for herbal medicines, therefore regulatory Some compounds belonging to the alkenylbenzene group
measures for herbal medicines need to be standardized are estragole, eugenol, safrole, myristicin, elemicin,
and strengthened at the global level to ensure that they trans-anethole, and β-asarone (BA) (48, 49). Safrole,
are safe for consumption and of acceptable quality (3). a hepatocarcinogen, is metabolised to a carcinogenic
Local government support, particularly financial, is metabolite, 1’-hydroxysafrole. In addition, safrole forms
essential to increase the capacity for laboratory testing ligands with cytochrome P-448 and P-450, which results
of herbal products. More importantly, manufacturers of in an increase in hepatic cytochrome P-448 and loss
local herbal products must be responsible for ensuring of cytochrome P-450 activity. In addition, safrole also
high quality and safe TMHS, which includes the source causes loss of ribosomes, thus impairing glycoprotein
of raw materials, compliance with GMP requirements synthesis and contributing to the process of malignant
and testing of the final products. transformation (40, 50). In animal studies, safrole has
been found to be tumorigenic in rodents, particularly
Genotoxic and carcinogenic phytochemicals in the liver (i.e., hepatocellular carcinoma, adenoma, or
cholangiocarcinoma) (51).
Carcinogens are substances that can cause cancer in
humans and animals (39) through the mechanism of
carcinogenesis, which involves the transformation
of healthy cells into cancerous cells (21). Humans
are exposed to carcinogens through several ways
including lifestyle and behaviour (e.g., smoking and
alcohol consumption), environmental pollution (e.g.,
sun exposure and radition), viruses and bacteria
(Helicobacter pylori and human papilloma virus) and
food. There are four categories of carcinogenic food Fig 1: Structural formula of methyleugenol, estragole and safrole
(alkenylbenzene)
contaminants (34):
I. Compounds that are naturally occurring
Mal J Med Health Sci 17(SUPP8): 207-222, Oct 2021 211Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)
Table II: Overview of several phytochemicals with genotoxic and/or carcinogenic properties
Phyto-
Natural Level found in herbal prod-
chemical Compound Regulatory Status Toxicities data
occurrence ucts (μg/g)
group
Alkenyl- Asaron- Essential oils The Committee on Herbal Herbal infusions = 9.13, Asarones formed epox-
benzene es (α and of the Aristolo- Medicinal Products (HMPC) and food supplements = ide-derived DNA adducts
ß-asarones) chiaceae plant – Concentration of asarones 14.53 (average) (69) in primary hepatocytes of
families (Asarum in herbal medicinal products male Wistar rats (39);
europaeum Lin- should be kept to minimum; Oil from rhizome of A. cal-
né) and Acora- the preliminary acceptable amus administered to rats
ceae (Acorus), daily intake (ADI) of 2 μg/kg (unspecified) for 2 years re-
including Acorus bw/day or 15 μg/day (based on sulted in macroscopic and
calamus L. var. max. dietary intake) (68). microscopic liver changes,
calamus, Acorus and malignant tumour at
calamus L. var. the duodenal region at
angustatus Bess week-59 (70).
(67, 68)
Elemicin Essential oil of JECFA – priority for evaluation N/A Metabolic activation
Petroselinum of risk due to consumption of elemicin produced
crispum (71), of botanicals and botanical 1-hydroxyelemicin which
nutmeg (72), preparations has been given to formed Cys or NAC
Melaleuca brac- elemicin and other alkenyl- adducts in C57BL/6J
teate (73) benzene (74); mice and mouse and hu-
EFSA – Elemicin is reported as man liver microsomes (76)
to be a compound of concern
(75).
Estragole Artemisia Scientific Committee of Food 13.3 - 23.9 (78); Induced DNA damage in
dranunculus L., (SCF), EFSA - Use of estragole 70 - 241.56 x 103 (40); V79 Chinese hamster cells
Foeniculum vul- should be restricted (63); 302.6 (79); with the alkaline comet
gare Mill. subsp. HMPC - limit to 0.05 mg/ 1.4 – 252.1 (80). assay (81);
vulgare var. person/day for adults and Formed E3N2dG and E3N-
vulgare, F. vul- adolescent and 1.0 µg/kg bw 6
dA adducts in primary rat
gare Mill. subsp. for children (77). hepatocytes (82).
vulgare var.
vulgare, Illicium
verum Hook f.,
Melissa officina-
lis L., Ocimum
basilicum L.,
Pimpinella ani-
sum L. (77)
Methyl- Acorus calamus IARC - Group 2B (46); 4.8 - 128.6 (78); Formed DNA adducts (N2
eugenol L., Cymbopogon EMA - current use does not 0.07 - 1.60 (40); -MIE-dG) in human liver
nardus Rendl., pose significant cancer risk 33.2 - 575.4 (79); samples (84);
Myristica (83). 12.4 - 214.2(80). Induced DNA damage in
fragrans L., male F344 rats liver cells
Ocimum basi- enzyme modified Comet
licum L., Piper assays using (85).
betle L., Sassafras
albidum Nees.,
Syzygium
aromaticum (L.)
Merr. et Perry
(83)
Myristicin Myristica The Joint FAO/WHO Expert 33.9 - 440.1 (78); Not genotoxic to human
fragrans Houtt, Committee on Food Additives 64.6 - 1269.8 (79); HepG2 cells in neutral
Petroselinum (JECFA) - further research on 28.2 - 1160.3 (80). comet assay, alkaline com-
crispum, Pasti- low-level exposure in humans et assay and micronucleus
naca sativa (86) is warranted (87); assay (88).
The Council of Europe –
myristicin is suspected to be
genotoxic carcinogens (86).
Safrole Piper betle L., IARC - Group 2B (46); 3.8 - 22.2 (78); Induced formation of
Sassafras al- FDA – use as food and direct 130 – 3460 (40); micronucleus in RAW264
bidum Nutt., and addition are prohibited (92); 18.8 (80) cell line (94);
Cinnamomum SCF, EFSA – Use of safrole Safrole oxide increased
camphora L. (89) should be restricted (93). comet tail length and fre-
Areca catechu quency of micronucleated
(90), Piper sar- binucleated cells in HepG2
mentosum (91) human and FVB mice cells
(95).
CONTINUE
212 Mal J Med Health Sci 17(SUPP8): 207-222, Oct 2021Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)
Table II: Overview of several phytochemicals with genotoxic and/or carcinogenic properties (cont.)
Phyto- Com- Natural occurrence Regulatory status Level found in herbal prod- Toxicities data
chemical pound ucts (μg/g)
group
Benzopy- Couma- Tonka bean EFSA – Tolerable daily 2450 – 3610 (99) In a 2-year study, coumarin re-
rene rin (Dipteryx odorata) intake 0.1 mg/kg bw (96); sulted in increased incidences of
(96), Cassia bark FDA – Prohibited from renal tubule adenomas in male
(Cinnamomum direct addition or use as F344/N rats, alveolar/bronchio-
aromaticum) (97) human food (98); lar adenomas in male B6C3F1
IARC – Group 3 (46). mice, and alveolar/bronchiolar
adenomas, alveolar/bronchiolar
carcinomas, and hepatocellular
adenomas in female B63CF1
mice (100);
Minor effect in micronuclei
induction in human hepatoma
cells in vitro and did not induce
unscheduled DNA synthesis in
human liver cells in vitro (101)
Nitro- Aristo- Aristolochia spp IARC - Group 1 (46, 59); AAI: 2.1 – 594.8, AAII: 0.6 AA forms DNA adducts in in
phenan- lochic including Aristo- FDA - All species of Aristo- – 235.3 (20); vitro in experimental animals
threne acid I lochia fangchi, A. lochia are prohibited to be AAI: 8 – 40, AAII: 8 –210 and human tissue and mutagenic
carboxylic (AAI) debilis, A. contorta, present in food and health (106) in bacteria, cultured cells, and
acids and II and A. manshurien- supplements. Other species AAI: 21.6, AAII: 9.6 –10.5 rodents (111).
(AAII) sis (59) and Asarum known or suspected to (107);
spp (102, 103) contain AA (Asarum, Coccu- AAI: 11.1 - 337.6, AAII:
lus, and Thottea) are listed 5.4– 725.4 (108);
under the safety alert (104); AAI: 24.5 – 2607, AAII:
UK – Prohibits the use of the 12.1– 711.2 (109);
plant species Aristolochia AAI: 0.0194 – 944.569,
in herbal medicines, along AAII: 6.802 – 148.687
with a number of other (110).
species that were being
confused with Aristolochia
(105);
Malaysia – prohibits all
plants from Aristolochia
genus, however other plants
such as Asarum spp, Bra-
gantia wallichii R.Br. will
have to be tested negative
for AA prior to registration
(16).
Nor-ses- Ptaqui- Pteridium aquili- IARC – Ptaquiloside, Group NA Induced DNA damage in human
quiterpene loside num, Cheilanthes 3; Bracken fern, group 2B mononuclear leukocyte (Comet
glycoside sieberi, or Ony- (46) assay), with elevated structural
chium contiguum and numerical chromosomal
(112) aberrations and sister chromatid
exchange (113)
CONTINUE
Mal J Med Health Sci 17(SUPP8): 207-222, Oct 2021 213Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)
Table II: Overview of several phytochemicals with genotoxic and/or carcinogenic properties
Phyto- Com- Natural occurrence Regulatory Status Level found in herbal Toxicities data
chemical pound products (μg/g)
group
Pyr- Helio- Heliotropium spp, EFSA – Heliotrine is one of 0.0121 - 0.4526 (117) *; Grains contaminated with Heliotropi-
rolizidine trine including H. europaeum, 28 PAs that should be moni- 0.004 – 7.883 (118) um species have caused outbreak of
alkaloid H. rotundifolium, H. tored in food samples (116) 0019 – 1.29 (119)*; liver diseases in humans such as liv-
suaveolens, H. popovii 0.0059 –3.421 (78) *; er dystrophy (124), liver emaciation
H and H. circinatum 0.00042 – 3.121 (120) *; and ascites (125), and death (114);
(114, 115) 0 – 5.668 (121) *; Formed micronucleated poly-
0.201 (average); 3.27 chromatic erythrocytes in the liv-
(highest) (122) *; er of adult mice and foetuses (126);
0.00011 – 0.00477 (123) Induced chromosomal aberrations
*. in V79 Chinese hamster cells of
without metabolic activation (127)
Its metabolite formed DHP-derived
Lasio- Heliotropium lasiocar- IARC - Group 2B (46);
DNA adducts in calf thymus DNA (130);
carpine pum, H. europaeum,
Induced DNA double-strands breakage
and several other plant The EU CONTAM (Panel
and micronuclei in v79 cells (131);
species that belong in on the Contaminants in the
Induced liver tumours and angiosar-
the Boraginaceae family Food Chain) – monitor the
comas in male and female rats Fischer
(128) content (129);
344 rats, and hematopoietic tumours in
female rats, in a 2-years bioassay (132).
Formed micronucleated poly-
Mono- Crotalaria spp including IARC – Group 2B (46);
chromatic erythrocytes in the liv-
crota- C. spectabilis (133) and
er of adult mice and foetus (126);
li-ne C. retusa (134)
Formed DHP-derived DNA ad-
ducts in F344 rats liver cells (135).
Riddelli- Senecio spp, including S. IARC - Group 2B (46); Formed DNA adducts in liv-
ine riddellii, S. vulgaris, S. er cells of F344 rats (139);
aegypticus, S. ambrosi- NTP - ‘reasonably anticipat- Mutagenic in Salmonella typhimurium
oides (S. brasiliensis), S. ed to be a human carcino- strain TA100 (140).
spartioides, and gen’(138);
S. longilobus (136, 137). Malaysia – Senecio spp. is
banned from any herbal
formulation (16).
Sene- Senecio spp, including S. The EU CONTAM - monitor Formed DHP-derived DNA adducts in
cionine illiciformis, S. burchelli, the content (129); liver, kidney and lung of rats (142);
S. vulgaris, S. jacobaea,
Tussilago farfara, Petasites Malaysia - Senecio spp. is Did not show mutagenicity in Salmonel-
hybirdus (141) banned (16). la mutagenicity test (143).
* Total PA concentration | NA – data not available
Chronic exposure leads to hepatic megalocytosis and
veno-occlusive disease (VOD). Eventually, VOD will
progress to the final stage of chronic PA intoxication,
characterised by centrilobular congestion, necrosis,
fibrosis, and liver cirrhosis (52, 54). The IARC classified
lasiocarpine, monocrotaline and riddelliine as ‘possibly
carcinogenic to humans’ (2B) (46) . Similarly, the WHO
also recommended that the level of PAs in food should
be kept as low as possible (55).
Fig 1(b): Structural formula of riddelliine, lasiocarpine, Aristolochic acid (AA) (Fig 1c) and its derivatives belong
monocrotaline and senecionine to the group of nitrophenanthrene carboxylic acids.
It is commonly found in the Aristolochia, Bragantia,
Pyrrolizidine alkaloids (PAs) (Fig 1b) are naturally
and Asarum species (56) which are widely used in the
occurring heterocyclic phytotoxins (52, 53). They are
Chinese community as traditional medicines to treat
found in numerous plant species, particularly in the
a variety of diseases, such as urinary tract infections,
Asteraceae, Fabaceae, and Boraginaceae families, and
oral ulcer, upper respiratory tract infections, eczema,
are widely distributed in the environment (54). Some
bronchitis, pneumonia, heart failure, hepatitis and
compounds belonging to this group are rideliine,
oedema (57). Exposure to AA is associated with many
senecione, lasiocarpine, heliotrine, seneciphylline,
chronic kidney diseases, including aristolochic acid
lycopsamine, clivorine and monocrotaline (55). The
nephropathy, Balkan endemic nephropathy, upper
main organ targeted by PAs is the liver, whereby acute
tract urothelial carcinoma, chronic kidney disease,
poisoning of PAs is characterised by hepatotoxicity
urothelial cancer and end-stage renal disease (56, 58)
and haemorrhagic necrosis, hepatomegaly and ascites.
214 Mal J Med Health Sci 17(SUPP8): 207-222, Oct 2021Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)
. AAs have been shown to be nephrotoxic, genotoxic using the following keywords – scientific name of the
and carcinogenic and have been classified as group 1 plant (e.g., Areca catechu), genotoxic, and carcinogenic.
carcinogen by the IARC. (46, 59). Based on the screening. eleven (11) plants were found
to contain genotoxic and carcinogenic phytochemicals,
namely Alipinia galanga, Cinnamomum verum,
Myristica fragrans, Ocimum basilicum, Orthosiphon
aristatus, Piper betle, Piper sarmentosum, Citrus hystrix,
Chromolaena odorata, Gynura procumbens and Areca
catechu. These plants are frequently included as
ingredients in TMHS in Malaysia.
By using an official online database (QUEST3+ Product
Fig 1(c): Structural formula of aristolochic acid Search - https://quest3plus.bpfk.gov.my/pmo2/index.
php), hosted by the Malaysian national regulatory
authority, NPRA, the number of TMHS registered
Genotoxic and carcinogenic potential of Malaysian in Malaysia containing these plants species were
plants species and their associated cancer risk generated. However, it is important to note that the
search was conducted strictly using only one Binomial
A total of 76 herbal plants documented in the MHM were nomenclature of the plant, which is the scientific name
screened for presence of genotoxic and carcinogenic used under the title of the monograph (i.e., Alpinia
phytochemicals including AAs, alkenylbenzenes, galanga for lengkuas) and not the synonyms. The search
coumarin and PAs. Firstly, by using the MHM website, identified 381 registered products with one or more
the list of chemical constituents for all of the plant of the 11 plant species identified earlier as ingredients
species were screened for the presence of these (Table III). Using the same database, further search
compounds. Next, further search was performed using for registered TMHS containing plant species known
other databases which are ScienceDirect and PubMed, to have PAs and AAs was performed, (60, 61) namely
Table III: MHM plants species containing genotoxic and carcinogenic phytochemicals
Species (Family); Vernacular name(s) Summary of the traditional use(s) as Genotoxic and carcinogenic constit- No of
Part(s) used outlined in the MHM uent(s) registered
TMHS
contain-
ing the
species
Alpinia galanga Lengkuas, galangal, Java To alleviate and treat fever, headache, Methyleugenol (91) 40
(Zingiberaceae); galangal, greater galan- cough, and respiratory illness, digestive
Rhizome gal, Siamese ginger. illness including flatulence, indiges-
tion and vomiting, menstrual pain,
amenorrhoea, skin infection, and as
postpartum tonic.
Areca catechu Pinang, areca nut, areca Used to relief gastro-intestinal problems Safrole, hydroxychavicol, catechins. 97
(Arecaceae); Seeds palm, areca nut palm, and diarrhoea, fever and headache. With presence of lime (component in
betel palm, betel nut, betel quid), arecoline is hydrolysed
betel nut palm to arecaidine, a potent, cytotoxic,
mutagenic compound that promotes
tumour formation (144). A. catechu is
categorised in Group 1 by the IARC,
even without addition of betel quid or
tobacco (22)
Chromolaena Pokok kapal terbang, Used traditionally to treat intestinal Intermidine (53), supinine, lyco- 3
odorata (Asterace- pokok Jerman, Siam pains, colds, cough, malaria, smallpox psamine, rinderine, echinatine (145)
ae); Leaf weed, Jack-in-the-bush, and yellow fever. Also used to aid
Christmas bush, goat wound healing and bleeding.
weed;
Cinnamomum ver- Kayu manis, Ceylon For joint pains and mental health. Coumarin, methyleugenol (91) 31
um (Lauraceae); cinnamon, cinnamon,
Leaf and bark cinnamon tree or true
cinnamon.
Citrus hystrix Limau purut, Kaffir lime; Often included in jamu and ointment Safrole (leaf) (146) 17
(Rutaceae); Leaf, formulations. Externally used to eradi-
fruit, peel cate worm, as hair wash and to relieve
headache.
CONTINUE
Mal J Med Health Sci 17(SUPP8): 207-222, Oct 2021 215Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)
Table III: MHM plants species containing genotoxic and carcinogenic phytochemicals (cont.)
Species (Family); Vernacular name(s) Summary of the traditional use(s) as Genotoxic and carcinogenic constit- No of
Part(s) used outlined in the MHM uent(s) registered
TMHS
containing
the species
Gynura procum- Sambung nyawa, Used traditional for kidney ailments, Lasiocarpine, retrorsine, heliotrine, 6 (Gynura
bens (Asteraceae); dewa raja, akar sebiak, for diabetes and hypertension and for retronecine, senkirkine, seneci- spp)
Leaf, aerial part kacham akar, Mollucan treatment of dysentery phylline, senecivernine, erucifo-
spinach, longevity line-N-oxide, lycopsamine-N-oxide,
spinach, leaves of the senecionine-N-oxide, seneciphyl-
Gods line-N-oxide (147). The pres-
ence PAs in other Gynura species
including G. bicolor, G. japonica, G.
segetum and G. divaricata has also
been documented (148-150)
Myristica fragrans Buah pala, nutmeg. Used as a tonic for digestive stimu- Methyleugenol, safrole, myristicin, 156
(Myristicaceae); lation. Also given childbirth, used as elemicin, beta asarone (91)
Seed, seed coat aphrodisiac and treat dysentery. Exter-
nally applied for various pains.
Ocimum basilicum Selasih, common basil, Used for various of illnesses including Methyleugenol (91) 3
(Lamiaceae); Leaf lemon basil, sacred cough, flatulence, ringworms, insect
basil, sweet basil. bites, toothaches. Also used as in wom-
en after childbirth to regulate menses-
The decoction of O. basilicum plant
is used to treat cough and prevent
flatulence.
Orthosiphon ari- Misai kucing, Java tea; Used to treat venereal diseases in- Methyleugenol (91) 19
status (Lamiaceae); cluding gonorrhoea and syphilis. Also
Aerial part, leaves, used for minor urinary tract infections,
whole plant menstrual disorders, tonsillitis, eruptive
fever, influenza, rheumatism, diabetes,
hypertension, epilepsy, oedema, hepa-
titis and jaundice.
Piper betle (Pipera- Sirih, betel, betel pep- Used traditionally for halitosis and to Methyleugenol, estragole (91, 151). P. 2
ceae); Leaf per, betel vine. relieve mouth ulcer, Additionally, used betle is categorised in Group 1 by the
for wounds, applied as lotion for after- IARC, even without addition of betel
birth. The leaves are heated and applied quid or tobacco (22)
on the chest to relieve cough. Also used
to treat stomach ache.
Piper sarmentosum Kadok, kadok batu, To relieve bone pain. Also used on chil- Methyleugenol, myristicin, safrole, 7
(Piperaceae); Leaf wild betel leaf. dren for headache and as an embroca- elemicin (91)
tion for tinea.
Borago officinalis, Emilia sonchifolia, Tussilago farfara sold in the Malaysian market may contain ingredients
and Asarum spp. The search identified 28 products that can induce cancer formation.
containing B. officinalis, 1 product containing E.
sonchifolia, 70 products containing T. farfara and 54 Genotoxic and carcinogenic compounds are present
products containing Asarum spp. In total, this search in wide range of plants and spices used on daily basis
identified 534 registered TMHS with plant species known in cooking (e.g., nutmeg contains methyleugenol), as
to contain genotoxic and carcinogenic phytochemicals foods (e.g., parsley contains elemicin and myristicin)
as ingredients. Another important point to consider is and beverage (e.g., PAs in rooibos tea) (40, 62). Due
that many of TMHS in the Malaysian market are poly- to their genotoxic and carcinogenic properties, the
herbal, meaning that they contain more than one type Scientific Committee on Food suggested restrictions in
of plant species. In fact, several products contain more the use of alkenylbenzene (51, 63). In an investigation
than one ingredient with genotoxic and carcinogenic by Herrmann, Schumacher (64), it was found that the
phytochemicals, for instance, one product was found to exposure to methyleugenol results in significant levels
contain 16 different herbals and four of the ingredients of hepatic DNA adducts in the human liver. This
which are known to have genotoxic and carcinogenic demonstrates that regular consumption, i.e., chronic
phytochemicals, namely Acorus calamus, Myristica exposure to these compounds even at low amounts, is
fragrans, Areca catechu and Piper betle. These findings, associated with cancer risks. Therefore, the use of these
while preliminary, suggests that some of the TMHS being herbs as traditional medicines or herbal supplements,
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