Review Article Chemical Composition, Pharmacological, and Toxicological Effects of Betel Nut

Page created by Marc Mclaughlin
Review Article Chemical Composition, Pharmacological, and Toxicological Effects of Betel Nut
Evidence-Based Complementary and Alternative Medicine
Volume 2021, Article ID 1808081, 7 pages

Review Article
Chemical Composition, Pharmacological, and Toxicological
Effects of Betel Nut

          Xiaoxiao Chen ,1 Yongzhi He ,1 and Yanru Deng                                  2

            College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine,
            Tianjin 301617, China
            College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China

          Correspondence should be addressed to Yanru Deng;

          Received 25 July 2021; Accepted 7 August 2021; Published 18 August 2021

          Academic Editor: Songwen Tan

          Copyright © 2021 Xiaoxiao Chen et al. This is an open access article distributed under the Creative Commons Attribution License,
          which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
          Betel nut, the fruit of Areca catechu L, has a long medical history in Southeast Asia. It is native to Malaysia and is cultivated and
          processed extensively in subtropical regions, such as South China and India. Betel nut almost appears as a “snack” in various
          occasions in most parts of China. Clinically, betel nut can play a certain pharmacology role and was used in malaria, ascariasis,
          arthritis, enterozoic abdominalgia, stagnation of food, diarrhea, edema, and beriberi. The nervous excitement of betel nut chewing
          has made it gradually become popular. However, chewing betel nut can induce oral submucosal fibrosis (OSF) and oral cancer
          (OC). At the same time, long-term chewing of betel nut also causes inhaled asthma, sperm reducing, betel quid dependence
          (BQD), and uterine and esophageal cancers. The main components of processed betel nut are the goal of this review. This study
          will mainly start from the pharmacological activity and toxicology study of betel nut in recent years, aiming to seek its advantages
          and disadvantages. In the meantime, this study will analyze and emphasize that betel nut and arecoline are the high-risk factors for
          oral cancer, which should arouse attention and vigilance of the public.

1. Introduction                                                          2.1. Alkaloids. The alkaloids in betel nut are the main
                                                                         active ingredients in research currently, while arecoline
Betel nut is the dried seed of the fruit from the Areca palm,            (methyl 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylate)
which is cultivated particularly in South and Southeast Asian            is considered the most important alkaloid in betel nut. It is
countries. According to the statistics, India, Malaysia, and             the main active ingredient and also the major toxic com-
Bangladesh have the world’s largest annual production in the             pound. The total alkaloid content of betel nut is estimated
world. Meanwhile, betel nut is an important traditional                  between 0.3% and 0.7%. The alkaloids also include arecai-
Chinese medicine (TCM), which has been used since an-                    dine, arecoline, arecolidine, guvacoline, guvacine, areca-
tiquity [1]. It is estimated [2] that about more than 600                tannin A1, arecatannin A2, isoguvacine, homoarecoline,
million people chew and eat betel nut. In addition to its                nicotine, and dichroine [4]. Recently [5], there are two new
medicinal use, there is a widespread abuse of addiction of               alkaloids, acatechu A and acatechu B (as shown in Figure 1),
betel nut, which is considered the fourth most used                      which are separated from betel nut and obtained their
stimulant.                                                               structures, and the study of the component in betel nut like
                                                                         alkaloids is still deepening.
2. Chemical Composition                                                      Arecoline is a pyridine-type alkaloid which can quickly
                                                                         cross the blood-brain barrier and that depends on its
So far, a variety of chemicals have been identified from betel            chemical structure [6], which lacks quaternary ammonium
nut, including alkaloids, tannins, flavonoids, triterpenoids,             ions compared with methacholine and has higher lip-
steroids, and fatty acids [3].                                           ophilicity, so it can cross the cell membrane into the body
Review Article Chemical Composition, Pharmacological, and Toxicological Effects of Betel Nut
2                                                                    Evidence-Based Complementary and Alternative Medicine

better. In each period of betel nut from young fruit to mature                           O                                   OH

and then to processing and placement, the content of                                                                              OCH3
arecoline changed accordingly. The general trend is that the                                                O
content will decrease after the peak of ripeness [7].                               OH                                  O    O
                                                                           O                                    O

                                                                     HO                                   NH2
                                                                                        OH                      HO           OH
2.2. Tannins. Tannin is the major component which makes                        OH                                       OH
betel nut bitter and astringent. Proanthocyanidins are the                 acatechu A                           acatechu B
main tannin component of betel nut, including catechins,
                                                                          Figure 1: Chemical structures of acatechu A and B.
arecatannin, and proanthocyanidin A and B [8, 9].
                                                                    3.2. Antiparasitic and Antibacterial Effects. Some of the
2.3. Flavonoids. Flavonoids [9], with various biological ac-        examples are antimalaria, treatment of leprosy, and anti-
tivities such as antibacterial and antitumor, are also isolated     bacteria. Chusri et al. [20] investigated the biological activity
from betel nut. The main classes of flavonoids in betel nut are      of traditional herbal formulas to heal wounds and found that
isorhamnetin, chrysoeriol, luteolin, quercetin, glycyrrhizin,       ethanol extracts containing betel nut and other four herbs
jacareubin, flavan-3-ol, flavan-3,4-diols, 4′,5-dihydroxyl-           can play an antibacterial role including against Staphylo-
3′,5′,7-trimethoxyflavone, and 5,7,4′-trihydroxy-3′,5′-              coccus aureus (SA), methicillin-resistant Staphylococcus
dimethoxydihydroflavone [10, 11].                                    aureus (MRSA), and so on. It also has significant antioxidant
                                                                    capacity for scavenging hydroxyl-free radicals.
                                                                         In addition, Wang et al. [21] studied the anticoccidial
2.4. Triterpenoids and Steroids. Betel nut also contains tri-
                                                                    effects of Areca nut extract (ANE) on coccidiosis, which
terpenoids compounds, including isotic acid and its deriv-
                                                                    showed that ANE could make the food consumption of rats
atives and 3β-acetylursolic acid in betel nut, as well as
                                                                    and the mucosal damage improved. It explains that the betel
aromatic alcohol, aromatic methyl ether, fernenol, aroin,
                                                                    nut has a certain extent anticoccidial activity and beneficial
cyclic altonil, and cycloartenol [12]. He et al. extracted
                                                                    effect on tissue damage caused by coccidiosis.
arborinol, fernenol, and arundoin from betel nut [13]. The
steroidal compounds are β-sitosterol, cycloartenol, stigmata-
4-en-3-one, and 22-dien-3-ol [9].                                   3.3. Nervous System Effects. Betel nut can act on the nervous
                                                                    system and has the effects of antiaging, improving learning
2.5. Fatty Acids. It is normal to use supercritical fluid ex-        and memory. Arecoline has an acetylcholine-like effect,
traction (SFE) to distill fatty acids and use GC/MS to analyze      which can activate M receptors, thus stimulating the
volatile components in betel nut [14]. According to the             parasympathetic nerves. At the same time, arecoline also has
study, there are lauric acid, nutmeg acid, palmitic acid,           an inhibitory effect on gamma-aminobutyric acid (GABA),
stearic acid, oleic acid, hexadanic acid, and (E,E)-2,4-dec-        which can bring delight and excitement. After arecoline
adienaldehyde from the betel nut peel [15].                         enters the oral cavity, it will have a mild systemic choline
                                                                    effect [22]. Ono et al. [23] established an AD model in aged
2.6. Other Chemical Compounds. Studies of the betel nut             rats and gave them 10 mg/kg arecoline for 6 consecutive
composition yet contain multiple categories of compounds,           days. Experimental results found that this can improve the
for instance, He et al. [13] found chrysophanic acid and            cognitive performance of elderly rats, which shows that
physcione. The polysaccharide in the betel nut is about             arecoline has a certain pharmacological activity in im-
18.7%, mainly galactose and sucrose, and plays a main               proving some symptoms of Alzheimer’s disease (AD).
antioxidant role in betel nut. Besides, resveratrol [16], erulaic   Furthermore, the research results of Asthana [24] showed
acid, ferulic acid, hervanonic acid, and deoxymethyl-io-            that arecoline has a certain pharmacological effect on en-
dinated lutein acrylic acid were also isolated from betel nut       hancing the memory of AD patients.
seeds. Table 1 shows that the ingredients of betel nut.
                                                                    3.4. Cardiovascular Effects. It can be used as an antihy-
3. Pharmacological Effects                                          pertensive and diuretic. Some studies believe that betel nut is
                                                                    an herbal medicine with antihypertensive and blood lipid-
3.1. Digestive System Effects. Salehi and his colleagues [18]
                                                                    lowering activities. Chewing betel nut will cause accelerated
summarized the digestive system effects of betel nut, for
                                                                    heartbeat, temperature rising, and heavy sweating within a
example, insect repellents, digestive function enhancers,
                                                                    certain period of time, promoting blood circulation. The
treatment of diarrhea, constipation, antiheartburn, ulcers,
                                                                    research of Inokuchi [25] is suggested that the extract of
and dyspepsia, and also treat gastrointestinal inflammation,
                                                                    betel nut has good hypotensive activity.
flatulence, hyperemesis gravida, and so on. It has been
confirmed that arecoline can stimulate the sympathetic
nerve, stimulate the choline M receptor, promote the in-            3.5. Other Effects. Some researchers have begun to study the
crease of human saliva secretion, sweating, and excitement          active ingredients in betel nut that inhibit α-glucosidase [26].
and gastrointestinal peristalsis, and help to improve human         Arecoline is considered a natural α-glucosidase inhibitor to
digestive function [19].                                            treat postprandial hyperglycemia in diabetic patients. In
Evidence-Based Complementary and Alternative Medicine                                                                          3

              Table 1: Ingredients of betel nut [17].            vitro analysis, Nouri et al. [27] confirmed that the extract of
Classification                      Ingredient name
                                                                 betel leaves with different dissolvents can provide inhibitory
                                                                 effects on key enzymes (α-amylase and α-glucosidase) as-
                                                                 sociated with type 2 diabetes and hyperglycemia. This allows
                                    Arecatannin a1               us to determine that betel nut polyphenol has the phar-
                                    Arecatannin a2               macological activity of lowering blood sugar, and it is based
                                      Arecolidine                on the assumption that it plays a role in lowering blood sugar
                                        Arecoline                by inhibiting the activity of α-glucosidase.
                                        Arecoline                    Lee [28] found that arecoline (50 μg/mL) can promote
                                    4-Quinazolone                the survival and growth of glial cells in vitro and found that
                                      α-Dichroine                arecoline in the body can stimulate local inflammation,
                                      β-Dichroine                which can promote the repair of severe peripheral nerve
                                        Guvacine                 damage.
                                                                     In addition, it can also treat beriberi, low back pain [29],
                                      Isoguvacine                and remove bad breath. It also includes the effects of
                       Methyl N-methylpiperidine-3-carboxylate   controlling sweating, edema, curing jaundice, and sedative
                       Ethyl N-methylpiperidine-3-carboxylate    effects [18].
                                   Ethyl nicotinate
                                                                 4. Toxicological Effects
                                      Chrysoeriol                4.1. Bronchoconstriction. In vitro trials, arecoline is known
                                        Luteolin                 to stimulate parasympathetic nerves and cause bronchial
Flavonoids                             Quercetin                 smooth muscle contraction, which is equivalent to a tenth of
                                      Glycyrrhizin               acetylmethylcholine. Taylor et al. [30] found that in the
                                                                 double-blind trial, subjects who chewed betel nut had
                                                                 bronchocontraction in different degrees. In the trials of four
                                                                 Bangladeshis asthmatic patients (AAPs) that chew betel nut
                             Procyanidin A1, B1, B2, B3
Tannins                       Arecatannin A1, A2, A3
                                                                 regularly, there was one showing FEV1 that decreased 30%
                                 Arecatannin B1, B2              with symptoms of chest tightness within 150 minutes of
                                   Arecatannin C1                chewing. It is speculated that betel nut contains arecoline,
                                        3-Carene                 which acts as cholinergic alkaloids that stimulates the dose-
                                    Procurcumenol                related bronchocontraction.
                                     Ursonic acid
                                3-Acetylursolic acid,
Terpenoids                                                       4.2. Central Nervous Toxicity and Addiction. Adriane [31]
                               Arborinol methyl ether            found that when the neuroleptic drugs combine with betel
                                        Fernenol                 nut, the extra propyramidal effect will be aggravated, and the
                                       Arundoin                  combination of betel nut with trifluorothiotons and pro-
                                     Cycloartenol                pylene cycling can cause stiffness, mild dyskinesia, and
                               5, 8-Epidioxiergosta-6            mandibular tremor. Combination with fluorosis can cause
Steroids                            Beta-sitosterol              tremor, stiffness, and sensory abnormalities, and combi-
                                     22-Dien-3-ol                nation with prednisone and salbutiamine can cause asthma.
                                Stigmasta-4-en-3-one                 Arecoline, a potentially addictive component of betel
                                   2-Lauroleic acid              nut, is an oxidative inhibitor that suppresses monoamine
                                    Arachidic acid               oxidase A(MAO-A). Thus, it can prevent the decomposition
                               Cis-4-dodecenoic acid
                                                                 of neurotransmitters, increasing the concentration of do-
Fatty acids                   Cis-9, cis-12-linoleic acid
                                     Myristic acid               pamine and serotonin in the brain, thereby bringing eu-
                                       Oleic acid                phoria and happiness [32].Consequently, many betel nut
                                     Palmitic acid               chewers occur withdrawal symptoms after a long-term
                                        Vanillin                 consumption of betel nut, which is as difficult to quit
                                    Alpha-terpineol              completely as tobacco. Withdrawal syndrome is character-
                                    Benzyl alcohol               ized by mood swings, anxiety, irritation, inattention, sleep
                                      Capric acid                disorders, and increased appetite. According to the statistics,
                                     Caproic acid                there are a large number of betel nut consumers around the
                                      Resveratrol                world which has the betel quid dependence (BQD). Win-
                                      Quinic acid                stock et al. [33] reported that part of the subjects had a
                                      Dicoumarin                 withdrawal reaction after stopping the betel nut chewing,
4                                                                 Evidence-Based Complementary and Alternative Medicine

with an average dependence severity of 7.3. Ko et al. [34]       such as inducing malignant tumors of the esophagus and
concluded by a systematic review that the neurological and       tongue in animal experiments [39].
pharmacological mechanisms behind BQD may be related to
brain’s reward, cognitive and impulsive system intercon-
                                                                 4.5.1. Oral Carcinogenesis. In recent years, an increasing
nection. Arecoline increases the level of brain serotonin and
                                                                 amount of data indicate that the habit of betel nut chewing is
norepinephrine, showing that it can prevent the decom-
                                                                 harmful to human oral health, even caused oral cancer,
position of neurotransmitters and improve dopamine (DA)
                                                                 resulting in death or severe facial distortion [43] (as shown in
and 5-HT levels in the brain.
                                                                 Figure 2). It has been shown that the appearance of oral cancer
                                                                 is closely related to unhealthy oral habits, including betel nut
4.3. Reproductive Toxicity. Recently, Wu [35] found that         chewing [44]. There are a series of studies that have found that
betel nut and arecoline had reproductive toxicity on male        oral cancer is due to carcinogenic agents such as arecoline,
rats, including the decline of sperm amount, azoosperma-         active oxygen, and nitrosamines, which are highly related to
tism, and sperm morphological abnormalities, which lead to       human toxicology [45]. In experiments on the interaction
sperm function impaired. There is possibility that the extract   between those of are coline and human fibroblasts, the re-
of betel nut disturbs the sperm and human male repro-            searchers confirmed that alkaloids of betel nut stimulate col-
ductive ability. Yuan [36] reported that betel nut extract       lagen synthesis, of which the effects of arecaidine are
reduced the effect on human sperm motility, of which the          remarkable and in a concentration-dependent manner.
effect of arecoline is the most remarkable. Another study              Chewing betel nut can induce oral leukoplakia and oral
[37] showed that the ethanol extract of betel nut had an effect   submucosal fibrosis (OSF), while OSF is an oral cancer
on the weight of ovaries of female rats, which significantly      (OC) precancerous state. Currently, Murti et al. [46]
increased the possibility of abortion. In general, betel nut     considered that the consumption of betel nut is the re-
contains components that may lead to human reproductive          markable cause of OSF through ecological observations and
toxicity.                                                        case reports. The habit of chewing betel nut may cause oral
                                                                 precancerous lesions such as OSF with the possibility of
                                                                 malignant transformation [47]. When arecoline was ad-
4.4. Cytotoxicity and Genotoxicity. Lin et al. [38] confirmed     ministered in drinking water to GPT delta rats, the fre-
the effects of arecoline on the epigenome and evaluated the       quency of oral tissue mutations which were detected is at
mRNA expression of histone methyltransferase, acetyl-            2.5 times that of the untreated, showing a unique mutation
transferase, and demethylase in K-562 cells exposed to           spectrum. It is suggested that arecoline produces muta-
arecoline. In fact, arecoline makes the expression of related    tionally induced damage in the oral tissues of rats [48].
genes (M) that catalyze histone methylation, acetylation, and    Moreover, N-nitrogenous derivatives of arecoline are a
demethylation is altered. While, H3K9 methylation involves       significant carcinogenic factor, which tends to oral squa-
maintaining the stability of chromosomal structural and          mous hyperplasia in mice [49]. Wang et al. [50] examined
inactivation of autosomal gene expression. Available data        the RT-PCR and found that after removing HIF1A-AS1
indicate that arecoline-induced epigenic changes play a part     gene segment, the arecoline-stimulated migration capacity
in chemically mediated mechanisms of cytotoxicity and            in buccal mucosal fibroblasts (BMFs) was obstructed. Their
genotoxicity. Arecoline can induce DNA chain disruption,         results showed that arecoline may result to relatively
chromosome distortion, and sister chromatid exchange,            overexpress in OSF tissues compared to normal tissue
affect DNA repair, and cause oxidative stress, and its me-        counterparts and can activate BMFs, which may be one of
tabolites, arecaidine and arecoline-N-oxide, are also ge-        the pathogenic pathways of OSF. Lin et al. [51] found that
netically toxic [39] (Table 2).                                  OSF associated with chewing betel nut increases the chance
    Shih’s [40] study on the cytotoxicity of arecoline showed    of multiple oral cancers greatly. It is vital to prevent OSF
that arecoline increases cytochrome C release and activates      and stop chewing betel nut for reducing the morbidity of
the cysteine aspartate-specific protease related signaling        OC. A recent meta-analysis of Yang et al. [52] found that
pathway, inducing neuronal cell death. Inhibition of cell        the prognosis of patients with betel nut chewing habits was
proliferation after arecoline addition may be caused by cell     poorer than those not. Therefore, long-term betel nut users
death induced by cytotoxicity of arecoline. In addition, Yen     should be aware of the potential risk of cancer.
et al. [41] found that arecoline can inhibit AMPK, the AMP-
dependent protein kinase, through inducing intracellular
reactive oxygen substances, and it is responsible for per-       4.5.2. Risk of Other Cancers. Besides oral cancer that attracts
forming cell apoptosis.                                          public attention, arecoline may also be a contributing factor
                                                                 to esophageal, liver, lung, and other diseases. For example,
                                                                 Wu et al. [53] explored the association between chewing
4.5. Carcinogenicity. Arecoline, an important ingredient in      betel nut with liver cirrhosis (LC) and hepatocellular cancer
betel nut, has been regarded as a possible carcinogen for        (HCC). It was remarkable that betel nut caused the risk of LC
human beings by the International Cancer Research Insti-         and HCC increased by 4.25 times among subjects that still
tute [42]. IARC set betel nut as “Group2Bcarcinogens,”           chew betel nut and caused the risk of infection with hepatitis
which means “may be carcinogenic to humans.” It was also         B or hepatitis C. In fact, betel quid chewing has an increased
observed that arecoline increased the incidence of tumors,       synergistic effect on the risks associated with hepatitis B and
Evidence-Based Complementary and Alternative Medicine                                                                                  5

    Table 2: Summary of DNA damage by arecoline and its metabolites [39], (+) for positive results and (–) for negative results.
Compound                                         DNA breaks                                    Unscheduled DNA synthesis
                                             (+) Mice kidney cells                  (+) Early spermatid stages of Swiss albino mice cells
                                             (+) Human oral cells                                    (+) Hep-2 cells
Arecoline                                       (+) Hep-2 cells                             (−) Human gingival keratinocytes
                                                 (+) 293 cells
                                           (−) Rat liver clone 9 cells
                                           (+) Rat liver clone 9 cells
                                             (+) Human oral cells
                                       (+) Immunodeficient NOD/SCID
Arecaidine                                   (+) Human oral cells
                                             (+) Human oral cells

       Oral Leukoplakia
                                                        Oral Submucous Fibrosis

                                                          Limited Mouth Opening


                                         Figure 2: Oral diseases associated with betel nut.

hepatitis C, yet stopping chewing BQ can reduce the im-             use. As one of the most effective components of betel nut,
mune risk caused by hepatitis C. Hence, it might be said that       arecoline has pharmacological activities such as antibacterial
chewing betel nut will induce liver cirrhosis and hepato-           and anthelmintic effects, reducing postprandial hyperglycemia
cellular cancer. According to reports [54], there is an as-         and improving Alzheimer’s disease. However, the harmful and
sociation between betel nut chewing and esophageal cancer,          side effects of betel nut cannot be ignored, including cyto-
which can significantly increase the risk of cancers.                toxicity and genetic toxicity, carcinogenicity (especially oral
                                                                    cancer), OSF, and addiction dependence. There are still a large
                                                                    number of people who are diagnosed with oral cancer, which is
4.6. Nephrotoxicity. Wang et al. [55] researched many               related to betel quid dependence (BQD) in consumers and
chronic kidney disease (CKD) patients and non-CKD pa-               improper promotion and guidance of enterprise. After clari-
tients and analyzed the effect of betel nut chewing on ne-           fying the toxicology mechanism and potential risks of areco-
phropathy. It showed that the betel chewer had a higher risk        line, the public should try to stay away from these substances.
of CKD than others, which can speculate that chewing betel              It is necessary to develop adjuvant therapeutic drugs
nut has nephrotoxicity and associated with CKD occurrence.          for betel nut withdrawal syndrome of potential BQD
                                                                    cessation drugs. In areas like Taiwan, such dependence
5. Conclusion                                                       quit institutions have emerged. Furthermore, chewing
                                                                    betel nut is not the only carcinogenic factor; thus, the use
Through a series of studies, this review summarized the             of products, like electronic cigarettes, containing areco-
chemical composition of betel nut and pharmacology and              line should also be eliminated. In conclusion, the pro-
research progress in clinical application of betel nut. Edible      portion of betel nut as chewing snacks should be
betel nut is more toxic, staying longer in the mouth, and using     depressed gradually. The increased investment in research
it for a long time is more likely to cause dependence than          of betel nut effects is vital for future work, and betel nut
medicinal betel nut. The medicinal betel nut is generally weak      will play a more positive role in pharmacological and
in toxicity, with a small dosage and little harm to the human       medical fields through guidance and supervision rather
body. The difference between the two is mainly in the way of         than becoming an unregulated addictive substance.
6                                                                        Evidence-Based Complementary and Alternative Medicine

Conflicts of Interest                                                   [14] Q. U. Li-Jie, W. J. Liu, X. J. Qian, and A. D. Sun, “GC-MS
                                                                             analysis of essential oil of betel extracted by supercritical CO_
The authors declare that they have no conflicts of interest.                  2 extraction,” Science and Technology of Food Industry, vol. 8,
                                                                             no. 3, 2012.
Acknowledgments                                                         [15] F. Kiuchi, N. Miyashita, Y. Tsuda, K. Kondo, and
                                                                             H. Yoshimura, “Studies on crude drugs effective on visceral
This work was financially supported by the National Key                       larva migrans. I. Identification of larvicidal principles in betel
R&D Program of China (2019YFC1711000).                                       nuts,” Chemical and Pharmaceutical Bulletin, vol. 35, no. 7,
                                                                             pp. 2880–2886, 1987.
                                                                        [16] A. D. Kinghorn, J. M. Pezzuto, D. Lee, and K. Bhat, “Aro-
References                                                                   matase inhibitors from Broussonetia papyrifera,” Journal of
 [1] W. Peng, “Using the “target constituent removal combined                Natural Products, vol. 64, no. 10, pp. 1286–1293, 2003.
     with bioactivity assay” strategy to investigate the optimum        [17] W. Peng, Y.-J. Liu, N. Wu et al., “Areca catechu
     arecoline content in charred areca nut,” Scientific Reports,             L. (Arecaceae): a review of its traditional uses, botany, phy-
     vol. 7, Article ID 40278, 2017.                                         tochemistry, pharmacology and toxicology,” Journal of Eth-
 [2] A. D. Volgin, A. Bashirzade, T. G. Amstislavskaya et al.,               nopharmacology, vol. 164, pp. 340–356, 2015.
     “DARK classics in chemical neuroscience: arecoline,” ACS           [18] B. Salehi, D. A. Konovalov, P. Fru, P. Kapewangolo, and
     Chemical Neuroscience, vol. 10, no. 5, pp. 2176–2185, 2019.             J. Sharifi-Rad, “Areca catechu-From farm to food and bio-
 [3] J. L. Huang and M. J. Mcleish, “High-performance liquid                 medical applications,” Phytotherapy Research, vol. 22, 2020.
     chromatographic determination of the alkaloids in betel nut,”      [19] M. Kaushal, A. K. Mishra, B. S. Raju et al., “Betel quid chewing
     Journal of Chromatography A, vol. 475, no. 2, pp. 447–450,              as an environmental risk factor for breast cancer,” Mutation
     1989.                                                                   Research: Genetic Toxicology and Environmental Mutagenesis,
 [4] S. Sen, G. Talukder, and A. Sharma, “Betel cytotoxicity,”               vol. 703, no. 2, pp. 143–148, 2010.
     Journal of Ethnopharmacology, vol. 26, no. 3, pp. 217–247,         [20] S. Chusri, S. Settharaksa, J. Chokpaisarn, S. Limsuwan, and
     1989.                                                                   S. P. Voravuthikunchai, “Thai herbal formulas used for wound
 [5] M. Cao, H. Yuan, M. Daniyal et al., “Two new alkaloids                  treatment: a study of their antibacterial potency, anti-in-
     isolated from traditional Chinese medicine Binglang the fruit           flammatory, antioxidant, and cytotoxicity effects,” Journal of
     of Areca catechu,” Fitoterapia, vol. 138, Article ID 104276,            Alternative & Complementary Medicine, vol. 19, no. 7,
     2019.                                                                   pp. 671–676, 2013.
 [6] N. Serikuly, E. T Alpyshov, D Wang et al., “Effects of acute and    [21] D. Wang, L. Zhou, W. Li, H. Zhou, and G. Hou, “Anti-
     chronic arecoline in adult zebrafish: anxiolytic-like activity,          coccidial effects of areca nut (Areca catechu L.) extract on
     elevated brain monoamines and the potential role of                     broiler chicks experimentally infected with Eimeria tenella,”
     microglia,” Progress in neuro-psychopharmacology & biolog-              Experimental Parasitology, vol. 184, pp. 16–21, 2018.
     ical psychiatry, vol. 104, Article ID 109977, 2021.                [22] C. Maurizio and M. Raffaella, “Potential action of betel al-
 [7] Z.-Y. Cai, Y.-C. Li, L.-H. Li, and Z.-G. Chen, “Analysis of             kaloids on positive and negative symptoms of schizophrenia: a
     arecoline in Semen Arecae decoction pieces by microchip                 review,” Nordic Journal of Psychiatry, vol. 66, 2011.
     capillary electrophoresis with contactless conductivity de-        [23] M. Ono, Y. Minamoto, S. Shibata, and S. Watanabe, “At-
     tection,” Journal of Pharmaceutical Analysis, vol. 2, no. 5,            tenuating effect of arecoline and physostigmine on an im-
     pp. 356–360, 2012.                                                      pairment of mealtime-associated activity rhythm in old rats,”
 [8] Y.-T. Ma, F.-L. Hsu, S.-J. J. Lan, and C.-F. Chen, “Tannins             Physiology & Behavior, vol. 57, no. 1, pp. 189–191, 1995.
     from betel nuts,” Journal of the Chinese Chemical Society,
                                                                        [24] S. Asthana, N. H. Greig, H. W. Holloway et al., “Clinical
     vol. 43, no. 1, pp. 77–81, 2013.
                                                                             pharmacokinetics of arecoline in subjects with Alzheimer’s
 [9] Y. V. Chavan and R. S. Singhal, “Separation of polyphenols
                                                                             disease∗,” Clinical Pharmacology & Therapeutics, vol. 60,
     and arecoline from areca nut (Areca catechu L.) by solvent
                                                                             no. 3, pp. 276–282, 1996.
     extraction, its antioxidant activity, and identification of
                                                                        [25] E. Inokuchi, “Antihypertensive substance in seeds of areca
     polyphenols,” Journal of the Science of Food and Agriculture,
                                                                             catechu L,” Journal of Pharmacobio-Dynamics, vol. 10, p. 62,
     vol. 93, no. 10, pp. 2580–2589, 2013.
[10] X. Zhang, J. Wu, Z. Han, W. L. Mei, and H. F. Dai, “Anti-               1987.
     oxidant and cytotoxic phenolic compounds of areca nut              [26] S. K. Bhat, M. Sarpangala, and D. Ashwin, “Antilipidemic
     (areca catechu),” Chemical Research in Chinese Universities,            activity of arecanut, Areca catechu L.: a valuable herbal
     vol. 26, pp. 161–164, 2010.                                             medicine,” International Journal of Herbal Medicine, vol. 5,
[11] X. Shen, W. Chen, Y. Zheng et al., “Chemical composition,               no. 1, pp. 35–38, 2017.
     antibacterial and antioxidant activities of hydrosols from         [27] L. Nouri, A. Mohammadi Nafchi, and A. A. Karim, “Phy-
     different parts of Areca catechu L. and Cocos nucifera L,”               tochemical, antioxidant, antibacterial, and α-amylase inhib-
     Industrial Crops and Products, vol. 96, pp. 110–119, 2017.              itory properties of different extracts from betel leaves,”
[12] S. A. Saeed, S. Farnaz, R. U. Simjee, and A. Malik, “Triterpenes        Industrial Crops and Products, vol. 62, pp. 47–52, 2014.
     and B-sitosterol from piper betle: isolation, antiplatelet and     [28] S. C. Lee, C. C Tsai, C. H Yao, Y. M Hsu, Y. S Chen, and
     anti-inflammatory effects,” Biochemical Society Transactions,             M. C Wu, “Effect of arecoline on regeneration of injured
     vol. 21, p. 462S, 1993.                                                 peripheral nerves,” The American Journal of Chinese Medicine,
[13] X. X. He, Y. J. Li, X. P. Hu, C. X. Zhang, and J. L. Wang,              vol. 41, no. 4, pp. 865–85, 2013.
     “Isolation and structural identification of triterpenoids and       [29] M. S. Amudhan, V. H. Begum, and K. B. Hebbar, “A review on
     anthraquinones from pericarpium Arecae,” Traditional Chi-               phytochemical and pharmacological potential of Areca cat-
     nese Drug Research & Clinical Pharmacology, vol. 61, no. 11,            echu L. Seed,” International Journal of Pharmaceutical Sci-
     pp. 2631–2637, 2010.                                                    ences and Research, vol. 12, no. 8, 2012.
Evidence-Based Complementary and Alternative Medicine                                                                                         7

[30] R. F. H. Taylor, N. Al-Jarad, L. M. E. John, N. C. Barnes, and        [46] P. R. Murti, “Etiology of oral submucous fibrosis with special
     D. M. Conroy, “Betel-nut chewing and asthma,” The Lancet,                  reference to the role of areca nut chewing,” Journal of Oral
     vol. 339, no. 8802, pp. 1134–1136, 1992.                                   Pathology & Medicine, vol. 24, 2010.
[31] F. B. Adriane, “Herb-drug interactions,” Focus on Alternative         [47] R. Anand, C. Dhingra, S. Prasad, and I. Menon, “Betel nut
     and Complementary Therapies, vol. 355, pp. 134–138, 2000.                  chewing and its deleterious effects on oral cavity,” Journal of
[32] S. Graziano, L Orsolini, M. C Rotolo, R Tittarelli, F Schifano,            Cancer Research and Therapeutics, vol. 10, pp. 499–505, 2014.
     and S Pichini, “Herbal Highs: review on psychoactive effects           [48] M. Wu, G Xing, X Qi et al., “Assessment of the mutagenic
     and neuropharmacology,” Current Neuropharmacology,                         potential of arecoline in gpt delta transgenic mice,” Mutation
     vol. 15, pp. 750–761, 2017.                                                Research, vol. 748, pp. 65–9, 2012.
[33] A. R. Winstock, C. R. Trivedy, K. Warnakulasuriya, and                [49] N. G. Oliveira, D. L. Ramos, and R. J. Dinis-Oliveira, “Genetic
     T. J. Peters, “A dependency syndrome related to areca nut use:             toxicology and toxicokinetics of arecoline and related areca
                                                                                nut compounds: an updated review,” Archives of Toxicology,
     some medical and psychological aspects among areca nut
                                                                                vol. 95, pp. 1–19, 2021.
     users in the Gujarat community in the UK,” Addiction Bi-
                                                                           [50] Y.-K. Wang, C.-M. Liu, T. Lin, C.-Y. Fang, C.-C. Yu, and
     ology, vol. 5, pp. 173–179, 2010.
                                                                                C.-H. Yu, “Inhibition of HIF1A-AS1 impedes the arecoline-
[34] A. M. Ko, C. H. Lee, A. M. Ko, and Y. C. Ko, “Betel quid
                                                                                induced migration activity of human oral mucosal fibro-
     dependence mechanism and potential cessation therapy,”                     blasts,” Journal of the Formosan Medical Association, vol. 119,
     Progress in neuro-psychopharmacology & biological psychiatry,              no. 4, pp. 879–883, 2020.
     vol. 103, Article ID 109982, 2020.                                    [51] X. Lin, X Wu, A Gomaa et al., “Analysis of risk factors for
[35] P.-F. Wu, T.-A. Chiang, M.-T. Chen et al., “A characterization             multiple primary oral squamous cell carcinoma: a cohort
     of the antioxidant enzyme activity and reproductive toxicity in            study,” Clinical Oral Investigations, vol. 24, no. 9,
     male rats following sub-chronic exposure to areca nut ex-                  pp. 3147–3155, 2020.
     tracts,” Journal of Hazardous Materials, vol. 178, no. 1-3,           [52] J. Yang, “Do betel quid and areca nut chewing deteriorate
     pp. 541–546, 2010.                                                         prognosis of oral cancer? a systematic review, meta-analysis
[36] J. Yuan, D. Yang, Y. Liang et al., “Alkaloids from areca (betel)           and research agenda,” Oral Diseases, vol. 3, 2020.
     nuts and their effects on human sperm motility in vitro,”              [53] G. H.-M. Wu, B. J. Boucher, Y.-H. Chiu, C.-S. Liao, and
     Journal of Food Science, vol. 77, no. 4, pp. T70–T78, 2012.                T. H.-H. Chen, “Impact of chewing betel-nut (Areca catechu)
[37] J. Shrestha, T Shanbhag, S Shenoy et al., “Antiovulatory and               on liver cirrhosis and hepatocellular carcinoma: a population-
     abortifacient effects of Areca catechu (betel nut) in female                based study from an area with a high prevalence of hepatitis B
     rats,” Indian Journal of Pharmacology, vol. 42, pp. 306–311,               and C infections,” Public Health Nutrition, vol. 12, no. 1,
     2010.                                                                      pp. 129–135, 2009.
[38] P.-C. Lin, W.-H. Chang, Y.-H. Chen, C.-C. Lee, Y.-H. Lin, and         [54] S. Akhtar, “Areca nut chewing and esophageal squamous-cell
     J.-G. Chang, “Cytotoxic effects produced by arecoline cor-                  carcinoma risk in Asians: a meta-analysis of case-control
     related to epigenetic regulation in human K-562 cells,”                    studies,” Cancer Causes & Control, vol. 24, no. 2, pp. 257–265,
     Journal of Toxicology and Environmental Health, Part A,                    2013.
                                                                           [55] M. Wang, S.-Y. Yu, Z.-t. Lv, and Y. Yao, “Betel nut chewing
     vol. 74, no. 11, pp. 737–745, 2011.
                                                                                and the risk of chronic kidney disease: evidence from a meta-
[39] M. M. Marques, F. A. Beland, D. W. Lachenmeier,
                                                                                analysis,” International Urology and Nephrology, vol. 50, no. 6,
     D. H. Phillips, and K. Z. Guyton, “Carcinogenicity of acrolein,
                                                                                pp. 1097–1104, 2018.
     crotonaldehyde, and arecoline,” The Lancet Oncology, vol. 22,
     no. 1, pp. 19-20, 2020.
[40] Y.-T. Shih, P. S. Chen, C.-H. Wu, Y.-T. Tseng, Y.-C. Wu, and
     Y.-C. Lo, “Arecoline, a major alkaloid of the areca nut, causes
     neurotoxicity through enhancement of oxidative stress and
     suppression of the antioxidant protective system,” Free
     Radical Biology and Medicine, vol. 49, no. 10, pp. 1471–1479,
[41] C.-Y. Yen, M.-H. Lin, S.-Y. Liu et al., “Arecoline-mediated
     inhibition of AMP-activated protein kinase through reactive
     oxygen species is required for apoptosis induction,” Oral
     Oncology, vol. 47, no. 5, pp. 345–351, 2011.
[42] B. J. Dave, A. H. Trivedi, and S. G. Adhvatyu, “Role of areca
     nut consumption in the cause of oral cancers. A cytogenetic
     assessment,” Cancer, vol. 70, no. 5, pp. 1017–1023, 1992.
[43] B. Y. Hernandez, X Zhu, M. T Goodman et al., “Betel nut
     chewing, oral premalignant lesions, and the oral micro-
     biome,” PloS One, vol. 12, Article ID e0172196, 2017.
[44] M. Pawlicki, “Cancer of the oral cavity,” Oral Surgery, Oral
     Medicine, Oral Pathology, vol. 24, pp. 491–508, 2015.
[45] N. Adil, H. Ali, A. J. Siddiqui et al., “Evaluation of cytotoxicity
     of areca nut and its commercial products on normal human
     gingival fibroblast and oral squamous cell carcinoma cell
     lines,” Journal of Hazardous Materials, vol. 403, Article ID
     123872, 2021.
You can also read