Authors: Dr. Dipti Singh, Dr. Sudhanshu Aggarwal.

48 MIG, Shekhupura, Vikas Nagar, Aliganj, Lucknow.

ABSTRACT
lycopene is a red colored fat soluble carotenoid, discovered by Earnest et al in 1959, which gives tomatoes & several other fruits their deep red colors. More recently lycopene has attracted substantial interest among researchers due to its biological and physiochemical properties especially its antioxidant properties. It has been shown to have several potent anti-carcinogenic and antioxidant properties and has demonstrated profound benefits in chronic diseases. Thus, lycopene being a potent antioxidant with minimal or no reported adverse effects may have a potential role in the management of various oral mucosal lesions such as oral submucous fibrosis and leukoplakia.

INTRODUCTION
Carotenoids are natural pigments synthesized by plants and are responsible for the colors of fruits and vegetables. The dietary necessity and health benefits of the carotenoid, β-carotene, the precursor of vitamin A, have been recognized for many decades. Lycopene is the carotenoid that gives tomato its bright red color, and it is one of the major carotenoids in Western diets. It has been shown to have several potent anti-carcinogenic and antioxidant properties and has demonstrated profound benefits in precancerous lesions such as leukoplakia.¹

CHEMICAL PROPERTIES
Lycopene is an acrylic compound with 11 conjugated and 2 non conjugated double bonds. Lycopene like other carotenoids is a natural pigment synthesized by plants and microorganisms to absorb light during photosynthesis and to protect them against photosensitization. It is a noncyclic carotenoid having a molecular formula C40H56 and a molecular weight of 536.85 daltons. ²


PHYSIOLOGIC FUNCTION OF LYCOPENE
The biological activites of carotenoids, such as β-carotene, are related to their provitamin A activity within the body. Since lycopene lacks the β-ionic ring structure, it does not have any provitamin A activity. The biological effects of lycopene in humans have therefore been attributed to mechanisms other than vitamin A. Its various benefits on human health can be explained on its following properties: ³

1. Antioxidant Activity
Lycopene has the capacity to prevent free radical damage to cells caused by reactive oxygen species. Studies have shown that it reduces the susceptibility of lymphocyte DNA to oxidative damage, inactivates H2O2 and NO and protects cells from NO induced membrane damage and cell death. Lycopene exerts its antioxidant properties by two mechanisms- physical and chemical; and the efficacy of physical quenching greatly exceeds that of chemical.

Physical quenching involves the transfer of excitation energy from free radicals to lycopene resulting in ground state oxygen and excited/isomerized lycopene. This energy is dissipated through the rotational and vibrational interactions of the excited carotenoid with surrounding solvent to yield ground state carotenoid and thermal energy. In this process the lycopene remains intact and can be utilized in further quenching, and thus acts as a catalyst.
Chemical quenching, contributes less than 0.05% of total quenching results in final decomposition of lycopene.⁴

2. Inhibition of cancer cell proliferation (cell cycle)
a) Decrease in cellular cyclin D1 protein level
Lycopene has been found to inhibit proliferation of several types of cancer cells, including those of oral, breast, prostate, lung, and endometrium. It brings about a decrease in cellular cyclin D1 protein levels, which causes inhibition of cell cycle progression from G0/G1 to S phase, as cyclin D1 is a key regulator of this process. Moreover, cyclin D1 is known to act as an oncogene (a gene whose dysregulation causes normal cells to become cancerous) and is found to be over-expressed in many breast cancer cell lines as well as in primary tumors. Thus, the decrease in cellular cyclin D1 level by lycopene provides a mechanistic explanation for the anticancer activity of the carotenoid.⁵

3. Regulation of transcription
Transcription is the process whereby genetic information is carried from the DNA molecule via the RNA molecule acting as a messenger. This biochemical route leads to the formation of new proteins by the process called translation. Lycopene modulates the basic mechanisms of cell proliferation, growth factor signaling, and gap junctional intercellular communication.⁶

4. Hypocholesterolemic Effects
Fuhrman et al. examined the effect of carotenoids on macrophage cholesterol metabolism in comparison with the effect of low-density lipoprotein (LDL) cholesterol and of the cholesterol synthesis inhibitor, fluvastatin. However, unlike LDL-derived cholesterol, which also suppresses macrophage LDL receptor activity, lycopene and β-carotene augmented the activity of the macrophage LDL receptor, similar to the effect of fluvastatin.⁷

LYCOPENE IN ORAL CONDITIONS
a) Oral leukoplakia
Gupta PC et al. (1998) in their population based case control study observed a protective effect of tomato consumption in oral leukoplakia.⁸
A study conducted by Singh MP et al. (2004) at Belgaum, Karnataka showed lycopene to be efficacious in the treatment of oral leukoplakia. They also reported that daily dose of 8 mg of lycopene was more efficacious than 4 mg a day. This efficacy of lycopene in the management of leukoplakia was associated to its antioxidant properties.⁹

b) Oral submucous fibrosis
A study was conducted by Kumar et al. (2007). In this study fifty-eight patients with oral submucous fibrosis were randomly divided into 3 groups, evaluated weekly over a 2-month period. Patients of group A received 16 mg of lycopene, those of group B received 16 mg of lycopene along with biweekly intralesional steroid injections, and those of group C were given a placebo. They observed that the mouth-opening values for the patients showed an average increase of 3.4 mm, 4.6 mm, and 0.0 mm for patients in groups A, B, and C, respectively. And have concluded that lycopene can and should be used as a first line of therapy in the initial management of oral submucous fibrosis.¹⁰

c) Oral cancer
A case control study conducted in Uruguary (2000) on 238 patients with upper aerodigestive tract cancer and 494 controls, found that tomato intake was associated with reduced risk of 30% and had a protective effect of 57%. Lycopene was strongly associated with a reduced risk of 22%.¹¹
In Hebrew University, Jerusalem (2001), researchers discovered lycopene to kill oral cancer cells when added to culture. They believed it to be due to its ability to restore gap junction communication, which is believed to be destroyed in oral malignancies, suggesting its possible role in oral cancer management as an adjuvant therapy.¹²

d) Oral Lichen Planus
Though the exact role of free radicals in the pathogenesis of OLP is not established, studies have suggested oxidative stress to play a vital role in the same. Lycopene being a potent antioxidant may have an important role to play in the prevention and management of this disease entity. However, this aspect in the ongoing research of OLP management remains to be elucidated.⁴
Nagao T et al. (2001) reported significantly lower levels of serum lycopene in the patients with atrophic and erosive lichen planus as compared to healthy controls. Though, this was attributed to be an incidental finding or a result of probable reduced intake of lycopene rich food due to patients symptoms state, the role of lower levels of this antioxidant in the pathogenesis of this disease process can be ruled out, and lycopene supplementation may be used as a therapeutic modality for treatment of atrophic erosive lichen planus patients.¹³
Anshumalee N and Shashikanth MC (2007) conducted adouble blind, randomized, placebo controlled study in which lycopene, a potent antioxidant was found effective in the management of OLP as it produced statistically significant reduction in both the signs and symptoms of the disease. Two groups of 15 symptomatic OLP patients each, when treated with 8mg/day of lycopene or an identical placebo for 8 weeks, showed a significantly better overall treatment response in lycopene group with 11 patients showing a complete cure, and all 15 showing partial or complete relief, in contrast in placebo group only 4 showed complete cure and 10 partial to complete cure.

e) Gingivitis
Chandra et al. (2007) conducted a study to compare the effect of systemically administered lycopene as a monotherapy and as an adjunct to scaling and root planning in gingivitis patients. Twenty systemically healthy patients showing clinical signs were involved in the study. The subjects were randomly distributed between the two treatment groups: experimental group 8mg lycopene/day for 2 weeks: and control placebo for two weeks. Quadrant allocation within each group was randomized with two quadrants treated with oral prophylaxis and two quadrants not receiving any form of treatment. The results presented in this study suggest that lycopene shows great promise as a treatment modality in gingivitis. ¹⁴

TOXICITY AND SAFETY OF LYCOPENE
There is a dearth of information on the adverse effects of lycopene in humans. One case study reported the incidence of lycopenemia in a 61 years old woman who had consumed 2 L of tomato juice daily for several years. Although there was evidence of lycopene and fatty deposits in the liver, there was an absence of measurable hepatic dysfunction. Based on the various safety studies reviewed, no adverse effects were observed at the highest intake level provided, that is, 3 g/kg/d of dietary or formulated lycopene.¹⁵

CONCLUSION
The current dietary recommendation to increase the consumption of fruits and vegetables rich in antioxidants has generated interest in the role of lycopene in oral diseases prevention. However, the evidence thus far is mainly suggestive, and the underlying mechanisms are not clearly understood. Further research is critical to elucidate the role of lycopene in oral diseases and to formulate guidelines for healthy eating and disease prevention. Further studies should be done to evaluate its efficacy in oral diseases.

REFERENCES

1. Di Mascio P, Kairer S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys 1989;274(2):532-8.
2. Rao AV, Ray MR, Rao G. Lycopene. Advances in food and nutrition Research 2006;51:99-164.
3. Heber D, Qing YL. Overview of Mechanisms of Action of Lycopene. Exp Biol Med 2002;227:920–23.
4. Anshumalee N, Shashikanth MC, Shambulingappa P, Deepak U. Lycopenne: A Promising Antioxidant. JIAOMR 2007;19(04):458-63.
5. Levy J, Sharoni Y. The Functions of Tomato Lycopene and Its Role in Human Health. ABC 2004;62:49-56.
6. Aust O, Ale-Agha N, Zhang L, Wollersen H, Sies H, Stahl W. Lycopene Oxidation Product Enhances Gap Junctional Communication. Food Chem Toxicol 2003;41(10):1399-1407.
7. Fuhrman B, Elis A, Aviram M. Hypocholesterolemic effect of lycopene and carotene is related to suppression of cholesterol synthesis and augmentation of LDL receptor activity in macrophages. Biochem Biophys Res Commun 1997;233:658–62.
8. Gupta PC, Hebert JR, Bhonsle RB, et al. Dietary factors in oral leukoplakia and submucous fibrosis in a population-based case control study in Gujarat, India. Oral Dis 1998;4:200-6.
9. Singh M. Efficacy of oral lycopene in the treatment of oral leukoplakia. Oral Oncol 2004;40(6):591–6.
10. Kumar A, Bagewadi A, Keluskar V, BDS, Singh M. Efficacy of lycopene in the management of oral submucous fibrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:207-13.
11. Stefani ED, Oreggia F, Boffeta P, Pellegrini HD, Ronco A, Mendilaharsu M. Tomatoes, tomato-rich foods, lycopene and cancer of the upper aerodigestive tract: a case control in Urugury. Oral Oncology 2000;36:47-53.
12. Livny O, Kaplan I, Reifen R, Charcon SP, Madat Z, Schwartz B. Lycopene inhibits proliferation and enhances gap junction communication of KB-1 human oral tumor cells. J Nutr 2002;132:3754-9.
13. Nagao T, Warnakulsuriya S, Ikeda N, Fukano H, Yamamoto S, Yano M et al. Serum antioxidant micronutrient levels in Oral Lichen Planus. J Oral Pathol Med 2001;30:264-7.
14. Chandra RV, Prabhuji V, Roopa DA, Ravirajan S, Kishore HC. Efficacy of lycopene in treatment of gingivitis: A randomized placebo controlled clinical trial.2007;5(4):327-336.
15. Institute of Medicine (2000) Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. National Academy Press, Washington, DC.