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ORIGINAL RESEARCH Table of Contents   
Year : 2009  |  Volume : 20  |  Issue : 3  |  Page : 298-303
GST null genotype and antioxidants: Risk indicators for oral pre-cancer and cancer


Departments of Oral Medicine and Radiology, S.D.M. College of Dental Sciences and Hospital, Dharwad - 580 009, India

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Date of Submission28-Jul-2008
Date of Decision06-Feb-2009
Date of Acceptance30-Apr-2009
Date of Web Publication30-Oct-2009
 

   Abstract 

Objectives : This study was undertaken to detect the gene polymorphism of detoxification enzymes and estimate the antioxidant enzyme status in patients with oral cancer, oral leukoplakia and oral submucous fibrosis (OSF).
Materials and Methods : The GSTM1 and GSTT1 gene polymorphism was evaluated using polymerase chain reaction; the antioxidant enzyme was estimated using biochemical methods. Statistical analyses were performed using student t-test and odds-ratio to estimate relative
risk (RR).
Results : The RR at 95% confidence interval (CI) for GSTM1 and GSTT1 was statistically significant for all groups. The mean values of glutathione were significantly raised in all groups. The mean values of ceruloplasmin and malonaldehyde was statistically significant among cancer and OSF patients but was insignificant in smokers and cases with leukoplakia.
Conclusion : Several genes perform the same function which implies the need to test for several genetic polymorphisms to identify individuals at high risk. The level of antioxidant enzymes correlate with the degree of oxidative damage. The need for further studies is emphasised.

Keywords: Cancer, ceruloplasmin, glutathione, GSTM1, GSTT1, leukoplakia, malondialdehyde, oral submucous fibrosis

How to cite this article:
Bathi RJ, Rao R, Mutalik S. GST null genotype and antioxidants: Risk indicators for oral pre-cancer and cancer. Indian J Dent Res 2009;20:298-303

How to cite this URL:
Bathi RJ, Rao R, Mutalik S. GST null genotype and antioxidants: Risk indicators for oral pre-cancer and cancer. Indian J Dent Res [serial online] 2009 [cited 2019 Sep 20];20:298-303. Available from: http://www.ijdr.in/text.asp?2009/20/3/298/57365
Although the definitive cause of cancer is, as yet, unestablished, various risk factors such as genetic susceptibility, tobacco and alcohol consumption have been identified. It is well known that smokers and quid chewers do not necessarily develop cancer or precancerous states while the same can be found in individuals who are nonsmokers and quid chewers. Therefore, the possibility of genetic susceptibility or predisposition and alteration of the genes due to presence of carcinogens plays an important role in the development of these states. Most of the carcinogens are lipophilic and have a tendency to be converted into water-soluble hydrophilic compounds that are easily removed from the body through the excretory system. This conversion or 'detoxification' of these carcinogens is achieved through phase-II enzymes of which Glutathione S-Transferase (GST) is an important constituent. [1]

Glutathione S-Transferases are a family of multifunctional proteins which act as enzymes and bind proteins in various detoxification processes. They comprise of four classes, namely α, μ, π, and θ. [2],[3] GST μ contains five members designated as GSTM1 to GSTM5 and GST θ consists of GSTT1 and GSTT2 genotype. GSTs act to prevent initiation of carcinogenic process by inactivating or detoxifying electrophilic carcinogens. During the initiation and promotion stages, specialized forms of GSTs are expressed and initiated in preneoplastic and neoplastic cells. [4]

Development of the pathological process in most cases is closely related to cell injury. One of the important mechanisms of membrane damage is injury by free radicals, particularly by activated oxygen species. [5] They are chemical species that possess an unpaired electron in the outer (valence) shell of the molecule. [5] Accumulation of excess amount of these free radicals causes destructive effects on lipid biomembrane, sulfhydril bonds of proteins, and nucleotides of DNA. This will, in turn, cause DNA damage, enzyme inactivation, especially sulfhydril peroxidation of lipids within cellular and organellar membranes, followed by damage of endoplasmic reticulum, mitochondria, and other microsomal components. [5] It has been hypothesized that adverse effects of excess free-radical formation leads to cancer, atherosclerosis, ageing, and even exercise-associated oxidative damage. [5] The human body has developed several endogenous antioxidant systems to deal with the production of reactive oxygen species (ROS). [6] An antioxidant is a substance which, when present in low concentrations relative to the oxidizable substrate, significantly delays or reduces oxidation of the substrate. These systems can be divided into enzymatic and nonenzymatic groups. [6] The enzymatic antioxidants include superoxide dismutase, catalase, and glutathione peroxidase. The nonenzymatic antioxidants include the lipid-soluble vitamins, vitamin E, vitamin A or provitamin A (beta-carotene), the water- soluble vitamin C, and glutathione (GSH). [6] The enzymatic and nonenzymatic antioxidant systems are intimately linked to one another and appear to interact with one another. The complex interactions of these different antioxidant systems may imply that therapeutic strategies will depend on a combination therapy of various antioxidants rather than a single agent. [6]

In this context, the present study aims at detecting the frequencies of GSTM1 and GSTT1 null genotype and the antioxidant status (by measuring the levels of glutathione, ceruloplasmin, malondialdehyde) in oral cancer, leukoplakia, and oral submucous fibrosis (OSF).


   Materials and Methods Top


This hospital-based study was conducted in the Department of Oral Medicine and Radiology, S.D.M. College of Dental Sciences and Hospital, Dharwad and Karnataka Cancer Therapy and Research Institute, Navanagar, Hubli. The sample was constituted for 150 subjects, selected at random from these centers. The age range was between 21 and 75 years. Informed consent was obtained from the patients who participated in the study.

Thirty cases each of leukoplakia, OSF, and oral cancer- diagnosed clinically and histopathologically-were randomly selected for the detection of the null genotype of GSTM1 and GSTT1 and the measurement of antioxidant status of glutathione, ceruloplasmin, and malondialdehyde (MDA). Subjects with systemic diseases like diabetes mellitus, hypertension, cardiovascular diseases, and other diseases were excluded from the study. The control group, matched for age, sex, and socioeconomic status, comprised 60 individuals for estimating GSTM1 and GSTT1; 30 habit- free subjects and 30 habitual smokers for detecting the antioxidant status.

The patients with lesions had either smoking or chewing habits or a combination of both. All the subjects included were examined using mouth mirrors and explorers under adequate illumination. History and clinical findings were recorded in a specially prepared standard pro forma.

Procedure

A total of 5 ml of blood was drawn from the mid-cubital vein with necessary aseptic precautions in a 5-ml disposable syringe and transferred to sterile siliconized tubes containing ethylene diamine tetra acetic acid to prevent coagulation. The blood was centrifuged at 2,000 rpm for 7 min in a refrigerated centrifuge. Plasma and buffy coat were separated. Erythrocyte suspension was filtered through cotton wool filter to remove any remaining leukocytes. Leukocytes were used for DNA extraction. The red blood cells were washed with 0.15 M NaCl (Salt) solution twice after 1-10 dilutions. Washed erythrocytes were used for membrane lipid peroxidation (MDA) immediately, while plasma was used for estimation of glutathione and ceruloplasmin.

Evaluation of GSTM1 and GSTT1 polymorphism status using polymerase chain reaction (PCR) was performed based on the method described by Gronau et al. [7] Malondialdehyde was estimated based on the method described by Jain et al. [8] Beutler and Kelly's procedure was followed to determine the glutathione levels in blood. [9] The copper oxidase method was used to measure ceruloplasmin. [10]

Statistical analysis

The collected data was submitted for statistical analysis using Student's t-test and odds ratio to estimate relative risk (SPSS version 5 software packages used).


   Results Top


The 273 base-pair (bp) fragment and 480 bp fragments were amplified for detection of GSTM1 and GSTT1, respectively. [Table 1] shows the frequencies of the GSTM1 and GSTT1 null genotype for the different groups. The GSTM1 null genotype was present in 60% of the controls, 53.3% oral cancer patients, 50% of leukoplakia cases, and in 46.6% of the OSF cases. Similarly, GSTT1 null genotype was present in 75% of the controls, 66.6% oral cancer patients, 63.3% of leukoplakia cases, and in 63.3% of the OSF cases. The presence of wild genotype of GSTM1 in control patient number 6 and 7 and wild genotype of GSTT1 in patient number 7 and 9 is illustrated [Figure 1]. [Figure 2] shows the presence of GSTM1 wild genotype in all five patients and the presence of GSTT1 wild genotype in patient 3. The relative risk at the 95% confidence interval (CI) was estimated for GSTM1 and GSTT1 and found to be statistically significant (P < 0.05) for all three disease groups [Table 1].

Glutathione levels were significantly increased in all groups compared to controls. MDA levels were significantly increased in OSF and oral cancer groups compared to controls (P < 0.05). However, the increase was statistically insignificant in leukoplakia cases and smokers compared to controls (P > 0.05). Ceruloplasmin levels were significantly raised in OSF and oral cancer groups compared to controls (P < 0.05). A trend of increase in levels of enzymes was observed from leukoplakia, OSF to oral cancer, suggesting an increased amount of oxidative stress with severity of the condition. However, the values increase was statistically insignificant in leukoplakia cases and smokers compared to controls (P > 0.05) [Table 2]. On comparing the levels of antioxidant enzymes in the GSTM1 and GSTT1 null genotype individual, it was found that the levels MDA were increased in oral cancer and OSF cases in both GSTM1 and GSTT1 null genotype individuals, whereas no change was observed in leukoplakia cases. Similarly glutathione, levels were increased in GSTM1 and GSTT1 null genotype individuals with oral cancer, leukoplakia, and OSF. GSTM1 null genotype individuals with oral cancer and OSF showed higher levels of ceruloplasmin, and those with leukoplakia showed decreased levels. Similarly GSTT1 null genotype individuals with oral cancer and OSF showed higher levels of ceruloplasmin, and those with leukoplakia showed negligible change.


   Discussion Top


Tobacco use is a well-known risk factor for cancer and preneoplastic states. Cofactors in these states include alcohol, dietary factors, viral infection, genetic factor, and others. Three-fourths of all oral and pharyngeal cancers are caused by smoking and consumption of alcohol, with most cancers due to heavy consumption. [11]

Cigarette smoke contains several thousand chemicals of which 50 compounds are known carcinogens, including polycyclic aromatic hydrocarbons. Betel-quid chewing is a popular habit in India and many Southeast Asian countries. Although the composition of betel-quid varies in different geographic locations, it generally consists of betel nut (Areca catechu), piper betel leaf, and slaked lime with or without tobacco. At least six alkaloids are present in the betel nut itself, of which arecoline and arecadine have been suggested as possible carcinogens. [12]

The conversion of procarcinogens to carcinogens is achieved by phase I enzymes by oxidation. These reactive intermediates combine with electron deficient DNA bases to form DNA adducts which lead to mutation and initiate carcinogenesis. The interception and detoxification of these carcinogens is brought about by phase II enzymes of which GSTs are an important constituent. [13] This balance between phase I and phase II enzymes is thought to affect disease susceptibility in an individual.

GST null genotype frequency

The GSTM1 and GSTT1 genes are polymorphic in humans and deficiency in enzyme activity is caused by inherited homozygous activity of the GSTM1 or GSTT1 gene. Different ethnic groups show differences regarding the presence or absence of GSTM1 or GSTT1 gene which may influence the interpretation of various epidemiological studies.

Various studies on different population groups show a variation in the frequency of the GSTM1 and GSTT1 null genotype with respect to caste, ethnicity, population group, and socioeconomic status. [14],[15],[16],[17] In the present study, the frequency of the GSTM1 was 60% which falls within the range (26- 79%) reported by Roy et al. [17] Such comparisons should be guarded since India is a country with diverse populations. However, the frequency of GSTT1 null genotype was 75% which was almost twice the frequency (6-39%) reported by Roy et al. [15] The varying frequencies in the diverse study groups could be attributed to contrasting microevolution, differing exposure to various toxic substances and diet.

The GSTM1 enzyme enables the elimination of chemical carcinogens and GSTT1 is involved in the biotransformation of methyl halogenoids and ethylene oxide. [18] The presence of the null genotype results in lack of elimination of toxic carcinogens in the body leading to their accumulation and DNA adduct formation. Hence, part of the population that lacks this enzyme may be more susceptible to smoking-or alcohol-related diseases.

The present study indicates the association of GSTM1 null genotype with a slight increase in risk for developing oral cancer, leukoplakia and OSF-a finding supported by others. [15],[19],[20] In contrast, the absence of oral cancer risk in GSTM1 null genotype has also been reported. [5],[21],[22],[23]

The GSTT1 null genotype is also suggested to play a role in oral cancer [20],[24] and leukoplakia. [19] The present study has also identified an increased risk for oral cancer, leukoplakia, and OSF conferred by GSTT1 null genotype. Others, however, report no associated risk of GSTT1 null genotype individuals towards to oral cancer. [24],[25]

It may be summarized that studies concerning GSTM1 and GSTT1 polymorphisms present inconsistent results with some showing associated risks and others no risk with the disease states. This could partly be explained by the diverse ethnic backgrounds and lack of standard laboratory techniques employed in the different studies. Hence, further studies in this regard with large population size may be necessary. In the present study, we used an internal control-β globin-which was co-amplified in every sample and the mixed samples examined together, hence the effects of the laboratory techniques on our observations are likely to be minimal.

Gronau et al. estimated the GSTM1 and GSTT1 null genotype as well as the total GSTs activity in oral cancer patients. [6] These authors observed detectable enzyme levels of GSTM activity in four individuals, although there was no PCR product of the gene. This could be explained as the cross-reaction of antibodies used with other isoenzymes of GSTM1, such as GSTM2, or a compensation of the lack of GSTM1 by other enzymes, probably other isoenzymes of the GSTM group. The inconsistent observations could also be explained by the GST isoenzymes' ability to exhibit overlapping substrate specificities and deficiency of the GST isoenzyme may be compensated by other isoforms with utilization of alternative metabolic pathways. Another factor to be considered while assessing individual disease risk is the balance between phase I and phase II enzymes: Most polycyclic aromatic hydrocarbons first require metabolic activation by phase I enzymes to ultimately become a carcinogen, following which they are subjected to detoxification by the phase II enzymes.

Antioxidant status

Malondialdehyde is a carbonyl compound generated by lipid peroxidation during arachidonic acid metabol­ism for the synthesis of prostaglandins. Malondialdehyde has been demonstrated to play a vital role in the pathogenesis of several diseases and inflammatory processes. Increased levels of the enzyme in OSF and oral cancer compared to controls were noticed, which is in agreement with other reports. [27],[28] In one follow-up study on OSF patients, [27] high levels of MDA and low levels of beta-carotene were observed before treatment. After treating the patients with antioxidants, the levels of MDA decreased while those of beta-carotene increased.

Glutathione is a ubiquitous tripeptide found in virtually all the cells. It protects cells against the destructive effects of ROS. Serum levels of the enzyme are often raised in patients with both oral cancer and precancerous states and has been reported in OSF, leukoplakia, and oral cancer. [12],[29],[30] The underlying theory for raised levels of the enzyme in precancer and cancer patients is that carcinogen-altered cells have acquired increased resistance to the cytotoxic effects of xenobiotics and, hence, can selectively grow in a toxic environment relative to the normal cells. [30]

Ceruloplasmin is a glycoprotein with a polypeptide chain including 1,046 amino acid residues. This protein belongs to the group of acute phase reactants and is a principal copper containing protein of plasma. With an increase in oxidative stress, there is increase in the ceruloplasmin levels making it an important antioxidant enzyme. This has been supported by many studies on precancerous states and different cancers. [27],[28],[31] The raised values of the enzyme in serum of patients with lesions when compared to controls indicate an increased antioxidant defense in response to the toxic substances released by the tumor and preneoplastic cells. The increased values of enzymes in OSF compared to leukoplakia indicate increased antioxidant activity in this group, in response to the higher oxidative damage compared to the leukoplakia group as indicated by MDA values. Ceruloplasmin is an effective antioxidant and organisms might respond by raising the antioxidant efficiency of plasma, i.e. by elevating the enzyme levels. [32]

An interesting observation in the present study is that mean levels of all the three enzymes increased with severity of disease, i.e. from precancerous lesions and conditions toward malignancy. The increased oxidative stress in erythrocytes of precancer and cancer patients is indicated by the elevated MDA levels that can be used as a reliable marker of oxidative damage in these cells. The increased levels of GSH in erythrocytes may be in response to the toxins released by preneoplastically/neoplastically altered cells. It is believed that these erythrocytes are also resistant to oxidative hemolysis, indicating that they were adequately protected against any free radical damage if serum levels of other antioxidants are suppressed. The increased ceruloplasmin levels indicate the elevated antioxidant activity of the serum. [29]

Although we did not observe a strong association between GSTM1 and GSTT1 null genotype and oral cancer, leukoplakia, and OSF, one should consider that these genes are known to act simultaneously; hence absence of one might be made up for by another. Recent study by Duarte et al. has shown that GSTM1 null genotype may increase the risk for oral leukoplakia. [33] Therefore, testing several genetic polymorphisms simultaneously has the potential to identify individuals with a high disease risk. This has profound implication for prevention since such high risk individuals may be thoroughly screened.


   Acknowledgments Top


We are very thankful to Dr. Kishore Bhat, Hi-tech lab, Belgaum for his constant help during the entire study, Sriman Dr. Veerendra Hegde, President, S.D.M. Education Society, Ujire, and Dr. C. Bhaskar Rao Principal, S.D.M. College Dental Sciences for the encouragement.

 
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Correspondence Address:
Sunil Mutalik
Departments of Oral Medicine and Radiology, S.D.M. College of Dental Sciences and Hospital, Dharwad - 580 009
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9290.57365

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