Citrus Monoterpenes - American Chemical Society

Chapter 31

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Citrus Monoterpenes: Potential Source of Phytochemicals for Cancer Prevention Kotamballi N. Chidambara Murthy,*,1 G. K. Jayaprakasha,1 Shivappa M. Mantur,1,2 and Bhimanagouda S. Patil1 1Vegetable

and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University, College Station, Texas, U.S.A. 2Hi-Tech Horticulture Unit, University of Agricultural Sciences, Dharwad, India *E-mail: [email protected]

Dietary monoterpenes are non-nutritive volatile principles found in citrus and other regularly consumed plant constituents. Monoterpenes are gaining significant importance as major ingredients of functional food and constituents of prophylactic formulations due to their ability to stabilize the symptoms of chronic diseases including cancer. Among the monoterpenes in citrus, D-limonene is the most common bioactive compound ranging from 30-96% of total volatile oil. The citrus monoterpenes have shown inhibition of human cancer cells proliferation and tumors growth through various mechanisms such as, induction of detoxifying phase-II enzymes, altering the genes responsible for activation apoptosis, inhibition of growth proteins, cell cycle arrest and inhibition of hormonal activities. The advantage of D-limonene is that the metabolites are also found to be effective inhibitors of cancer cells. The major active metabolites of D-limonene, perillyl alcohol, perillic acid and limonene 1, 2-diol are known for the inhibition of human colon, breast and prostate cancer cells. Our research has demonstrated that volatile oil isolated from Citrus aurantifolia and C. senesis (rich in D-limonene and D-dihydrocarvone) is capable of inhibiting proliferation of human colon cancer cells by inducing apoptosis and inhibition of angiogenesis, a potential target for cancer chemoprevention. In this chapter, health attributes of dietary monoterpenes and their role in © 2012 American Chemical Society In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

chemoprevention of cancer is discussed with emphasis on citrus monoterpene D-limonene. Keywords: Apoptosis; colon cancer; citrus; essential oil; monoterpenes


Introduction Monoterpenes mainly present in volatile oils are used widely in food and pharmaceutical industry. They are also referred as ‘essential oils’ due their fragrance/essence. According to United Nation’s COMTRADE data base, global imports of essential oil was $2 billion in 2005. USA, France and UK were top three producers of the global essential oil (http://comtrade.un.org). Data from Caribbean community suggest that essential oil of orange constituted 10% of the total trade (www.caricom.org). More than 3000 essential oils are known and approximately 300 are widely used for different purposes. The world demand for essential oils, herbal extracts and natural fragrance blend is expected to increase by 4.3% by 2014, amounting to approximately $23.5 billion. World flavor and fragrance demand was more than $ 19 billion in 2009, of which 29% was from North America and 28% was from Western Europe. Recently, India and China have emerged as potential exporters of essential oils for future (1). Some of the commonly used essential oils of citrus species are from sweet orange (Citrus sinensis), bitter orange (Citrus aurantium L), lemon (Citrus limon), lime (Citrus aurantifolia), grapefruit (Citrus paradisi), bergamot (Citrus bergamia), mandarin (Citrus reticulata Blanco), tangerine (Citrus reticulata), and neroli (Citrus aurantium var. amara or bigaradia).

Chemistry of Citrus Monoterpenes Monoterpenes are class of terpenoids, which consist of two isoprene units with general molecular formula C10H16. These occur as cyclic or linear molecules and most of the monoterpenes are formed through rearrangements and oxidation of the original molecule. Majority of the monoterpene are secondary products from plants and only few are produced in animals and microorganisms (2). The monoterpenes are synthesized from geranyl pyrophosphate through oxidation, cyclization or rearrangement. Chemical structures of some of the biologically active dietary monoterpenes are shown in Figure 1A.

Extraction Techniques and Analysis of Monoterpenes from Citrus Extraction techniques and analysis of monoterpenes from citrus In laboratory and pilot scale citrus monoterpenes can be extracted by either by hydro-distillation techniques using Clevenger’s type apparatus, or Nickerson apparatus and supercritical extraction (3–6). Steam distillation is most commonly used in industries for production of volatile oil (6). The chemical composition of 546 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


volatile oils will be analyzed by Gas chromatography. In addition, NIR (near infrared)-spectroscopy was also used to analyze commercial citrus oils (7). Other techniques used for quantitative analysis of citrus oil are ATR/FT-IR (Attenuated Total Reflectance/ Fourier transform infrared) and NIR-FT Raman Spectroscopy (8).

Figure 1. A. Chemical structure of biologically active monoterpenes found in diet. B. Metabolites of D-limonene identified in rabbit (58) and C. Major D-limonene metabolites identified in human serum (59).

547 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Biological Activities of Monoterpenes Monoterpenes are known for number of biological activities, including antimicrobial and anti-fungal activity, enhancement of skin health, antiinflammatory activity, analgesic and properties of inhibition of cancer cells proliferation (9–12). The volatile monoterpenes are clinically used for pulmonary obstruction and acute bronchitis (13) . Numbers of monoterpenes rich volatile oils are explored for health benefits using in vivo and in vitro models, however very few are clinically studied. Some of the volatile oils clinically tested for their health benefits include, 1,8- cineole, standardized myrtol (mixture of 1,8- cineole, α-pinene and limonene), thyme oil and peppermint oil (14). Another major therapeutic area which utilizes monoterpene rich volatile oil is ‘aromatherapy’. It is most actively growing system of alternative medicine, which combines massage, counseling and use of plant aromas to treat various ailments (15). Some of the clinical investigations conducted on aromatherapy includes, use of lavender oil in peritoneal repair after child birth (16), lavender foot massage in intensive care unit (17), use of ylang and other oil in epileptic patients (18). These studies suggest that monoterpenes are capable of providing a wide range of health benefits. Monoterpenes are easily absorbed by the body and can cross the blood brain barrier efficiently (19). Therefore, the common effect of volatile oils are CNS mediated, sedation and stimulation (15). The most commonly used essential oil and their pharmacological actions are listed in Table 1.

Table 1. Pharmacological activity of monoterpenes rich essential oils Condition

Most commonly used volatile oil rich in monoterpenes

Reference

Sedative

Chamomile, Bergamot, Geranium, Lavender, Lemon, Marjoram, Rosewood, Sandalwood, Valerian

Referred in (15)

Stimulant

Basil, Jasmine, Chamomile, Patchouli, Peppermint, Ylang ylang

Referred in (15)

Anti-inflammatory

Eucalyptus Black cumin seed Lavandula angustifolia Mill. Tea tree oil Lippa multiflora Cymbopogon citrates Satureja hortensis L

(60) (61) (62) (63) (64) (65) (66)

Antipyretic

Lippa multiflora Calamintha sylvatica subsp. Artemisia caerulescens subsp. gallica

(64) (67) (68)

Induction of Anastasia in children

Sweet orange

(69)

Diuretic

Anthemis nobilis

(70) Continued on next page.



Table 1. (Continued). Pharmacological activity of monoterpenes rich essential oils Condition

Most commonly used volatile oil rich in monoterpenes

Reference

Lipid lowering

lemongrass oil

(71)

Anthelmienthic

Ocimum gratissimum Linn.

(72)

Antispasmodic and anti-diarrhoeal

Satureja hortensis L

(73)

Anti stress

Lemon oil

(74, 75)

Anti-conversant

Clove (Eugenia caryophyllata)

(76)

Antileishmania

Ocimum gratissimum

(77)

Hypotensive

Croton nepetaefolius, Mentha x villosa

(78, 79)

The monoterpenes from citrus are well known for their antimicrobial activity against wide range of organisms, including Helicobacter pylori (20, 21). Additionally, they have also demonstrated sedative, anti-stress, antidepressant activity, ability to potentiate the activity of anesthesia in children, (22) , anti-inflammatory (23) and mild aphrodisiac activity (24). Other health benefits claimed by the sellers of these products based on the non referred information include, antispasmodic, antiseptic, carminative, diuretic, cholagogue activity (25). One of the major monoterpene D-limonene, which is abundantly found in citrus species, has clinical significance for colon and breast cancer prevention (26).

Therapeutic Benefits of D-Limonene from Citrus The advantages of D-limonene are fast absorption and production of biologically active metabolites (27). Structure of the selected metabolites observed from rabbit urine and feces are shown in Figure 1 B and similar metabolites were also found in a human study. The LD50 value for D-limonene in male and female mice is 5.6 and 6.6g/kg body weight, respectively. The same is 4.4 and 5.1 g/kg body weight in case of male and female rats (28). The research from national toxicology program (NTP) has shown that administration of different doses (413-6,600 mg/kg) of D-limonene daily for five days/week for three weeks did not result in any signs of toxicity upto the dose of 1,650 mg/kg (29). In humans, except for increase in bowel movements, no abnormal or toxic symptoms were observed based on blood test, liver, pancreas and kidney test with administration of single dose of 20 g D-limonene (30). Based on the clinical investigation dose equivalent to 7.0 g of D-limonene was found to be safe for an average adult weighing 60 kg (27). D-limonene is listed in the code of federal regulations to be generally recognized as safe (GRAS) to be used as flavoring agent in food. Based on the information available the average intake of D-limonene by American is 16.2 mg/person/day (Avg. 60 kg person) (31). The 549 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


advantages with D-limonene is the fast and complete absorption by oral and other routes of administration, rapid metabolism and distribution in different organs (32). D-limonene and its metabolites are detected in serum, lung, liver, kidney as well as relatively higher concentrations are found in adipose tissues, including mammary of rats (33, 34). The half life of D-limonene in human is 12 -24 h and a major part is excreted through kidney (28). The major urinary metabolites of D-limonene in human are glucuronides of perillic acid, dihydroperillic acid, limonene-8,9-diol, and monohydroxylated limonene, perillic acid (27, 32). Some of the metabolites of D-limonene analyzed in human serum are as shown in Figure 1C.

Mode of Cancer Cells and Tumor Inhibition by Monoterpenes D-limonene constitutes a major compound (30-96%) in most of the citrus species. Minor monoterpenes are β-pinene, γ-terpene, α-pinene, myrcene and linalool representing less than 15% of total monoterpenes. Research on cancer prevention is focused mainly on D-limonene and its active metabolites, perillic acid and perillyl alcohol. Citrus monoterpenes have shown inhibition of lung, colon, liver, leukemia, mammary cancer cells proliferation and inhibition of chemically induced rodent mammary and pancreas carcinoma (3, 35–37). Number of research reports explaining the proliferation inhibition and tumor inhibition ability of monoterpenes from citrus was documented. Additionally these compounds have also shown inhibition of cancer cells through unique mechanisms such as, post translational isoprenylation of growth controlling Ras oncoproteins in pancreatic cancer cells (38). These Ras proteins are also known as small molecular weight G-proteins, which regulate survival and growth of the cells, whose dysregulation is known to cause cancer. Carvacrol, a principle monoterpene of many dietary components showed inhibition of human non-small cell lung cancer (NSCLC) cell line, A549 (39). Transgenic mouse embryonic NIH 3T3 fibroblast cells trasfected with D-limonene synthase gene from Japanese catnip (Schizonepeta tenuifolia) has shown induction of apoptosis in limonene producing cells. Induction of apoptosis in these cells were characterized by increase in apoptosis related Bcl-2 family proteins and decrease in the level of Bad and phosphorylated JNK (40). Menthol, a monoterpene found in mint and other plants has shown inhibition of 7,12-dimethylbenz (a) anthracene (DMBA)-induced mammary rat cancer when supplemented as 1% of daily diet (41). Menthol has also shown induction of apoptosis in human bladder cell lines T24 through inhibition of transient receptor potential melastatin 8 (TRPM8)-dependent pathway through alteration of intracellular calcium (42) Carvacrol from Origanum onites L. demonstrated inhibition of DNA synthesis in N-ras transformed mouse myoblast cells, CO25 (43). Calcium dependant inhibition of NFκB by perillyl alcohol was observed in WEHI-231 B-lymphoma cells (44). Phosphorylation of BRCA1 (breast cancer–associated gene 1) by a bicyclic monoterpene diol was observed in human keratinocytes and this phosphorylation is helpful in protection of cells against UNB-induced damages (45). Volatile oil from Schefflera heptaphylla (L.) rich in β-pinene 550 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


has been demonstrated to inhibit human skin, hepatic and breast cancer cells proliferation with IC50 values of 147.1 to 264.7 µM (46). Induction of phase-II enzymes, initiation of apoptosis, inhibition of post translational isoprenylation of cell growth-regulating proteins seems to play a major role in cancer inhibition by D-limonene and perillyl alcohol (26). Limonene also demonstrated antioxidant activity and protection of cells against oxidative stress by inhibiting H2O2 via increased activity of catalase and peroxidase enzymes (47). Ascaridole a monoterpene found in Croton regelianus Muell. Arg., a native plant of Brazil has shown inhibition of different cancer cells effectively with IC50 values of 4.2-23.7 ppm and inhibited mouse Sarcoma 180 Tumor at 50 and 100 mg/kg (48).

Citrus Monoterpenes and Colon Cancer Dietary perillyl alcohol and D-limonene have shown inhibition of azoxymethane (AOM) induced colon tumor at dose of approximately 1g/ kg body weight (49). Induction of apoptosis was also observed in the colon of these animals. D-limonene also showed similar effect on azoxymethane (AOM) induced F344 rat model. Treatment of 0.5% D-limonene in drinking water for a week before administration of AOM has resulted in significant (P90% of total monoterpenes) has shown differential inhibition of cancer cell proliferation (pancreatic, colon, breast and prostate). Based on the current knowledge on cancer chemoprevention, major targets of D-limonene to inhibit tumor and proliferation are summarized in Figure 2.

Figure 2. Major cancer related genes and enzymes targeted by D-limonene. The dark circle represents up-regulation/elevation of the activity or phosphorylation and white circle represents down-regulation. 552 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


In summary, D-limonene, a major monoterpene of citrus, is known for several health benefits including chemoprevention of cancer. D-limonene and its major metabolites such as, perillic acid, perillyl alcohol seems to act on various genes specific to cancer environment to prevent cell proliferation, tumor growth and metastasis. Some of the targets include induction of phase-II enzymes, cell cycle arrest, induction of apoptosis, inhibition of metastasis, anti-inflammatory, anti-angiogenesis and induction of antioxidant enzymes. D-limonene is listed as a GRAS agent, suggesting its non-toxic nature to normal cells. Therefore, D-limonene a major constituent of citrus volatile oil may serve as a potential chemopreventive agent for cancer of the colon and other organs.

Acknowledgments These results are based on the work supported by the USDA-CSREES # 200934402-19831 and # 2010-34402-20875 "Designing Foods for Health" through the Vegetable & Fruit Improvement Center. Support of Ms. Sanyogeeta M Bhaway for collection of literature is gratefully acknowledged.

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