|Year : 2014 | Volume
| Issue : 2 | Page : 154-158
Role of CYP2E1genetic polymorphism in the development of oral leukoplakia among tobacco users in North Indian population
S Gupta1, OP Gupta2, S Srivastava1
1 Department of Oral Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of General Surgery, Carrier Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Web Publication||7-Aug-2014|
Department of Oral Pathology, King George's Medical University, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Aim: The aim of the study to find out role of CYP2E1 genetic polymorphism in development of oral leukoplakia among tobacco users in North Indian population, this study was carried out at Department of Oral and Maxillofacial Pathology, King George's Medical University, Lucknow, UP. Study Design: Study include a total of 105 leukoplakia patients were genotyped for CYP2E1 polymorphism (93 males and 12 females; mean age ± SD: 47.5 ± 10.6) and 96 unrelated healthy controls (85 males and 11 females; mean age ± SD: 49 ± 11.1). All the patients had either reported for treatment of leukoplakia or were diagnosed with leukoplakia during routine oral examination. Results: A total of 105 leukoplakia patients and 96 controls were included in the study. The mean age of leukoplakia patients and control were 47 ± 10 and 51 ± 10 years respectively. The exclusive smokers comprised 62 (59%) leukoplakia patients and 53 (53%) controls. The exclusive smokeless tobacco users were 16 (15%) in leukoplakia patients and 27 (28%) in controls groups, while 27 (26%) leukoplakia patients and 16 (17%) controls have both types (smoking as well as smoke less) of tobacco habits simultaneously. Range of life time smoking exposure in leukoplakia and controls were (5-80 PY in both groups) but the mean smoking exposure in both groups were (leukoplakia: 28 ± 21.8 PY, control: 27: ±17 PY). But the mean smokeless tobacco dose in two groups were (leukoplakia: 150 ± 175 CY, controls: 137 ± 110 CY). Conclusion: All the results demonstrate an association between CYP2E1 genetic polymorphism and leukoplakia risk, premalignant lesion. It indicates that the CYP2E1 polymorphism, singly showed a protection towards the oral leukoplakia. Independent confirmation of this finding is required, and additional examination of the joint effect of CYP2E1genotype and other non-tobacco-related exposures is needed before more conclusive interpretation of our results can be made. This study demonstrates the importance of genetic variations in CYP2E1genes in susceptibility towards oral leukoplakia and it is conceivable that these variants will interact with environmental carcinogens and possibly some combinations of these genotypes will be at a high risk to oral leukoplakia.
Keywords: CYP2E, oral leukoplakia, PCR-RFLP
|How to cite this article:|
Gupta S, Gupta O P, Srivastava S. Role of CYP2E1genetic polymorphism in the development of oral leukoplakia among tobacco users in North Indian population. Indian J Cancer 2014;51:154-8
|How to cite this URL:|
Gupta S, Gupta O P, Srivastava S. Role of CYP2E1genetic polymorphism in the development of oral leukoplakia among tobacco users in North Indian population. Indian J Cancer [serial online] 2014 [cited 2019 Dec 9];51:154-8. Available from: http://www.indianjcancer.com/text.asp?2014/51/2/154/138266
| » Introduction|| |
The World Health Organization (1978) has defined oral leukoplakia as a white patch or plaque, which cannot be characterized clinically or pathologically as any other disease. Oral leukoplakia is a premalignant lesion, that is, a morphologically altered tissue that long has been considered to confer increased risk for the development of oral cancer, , squamous cell carcinoma is more likely to occur than in its apparently normal counterpart.  The reported annual malignant transformation of oral leukoplakia into oral squamous cell carcinoma (OSCC) is approximately 1-2%.  Several factors have been suggested to predict an increased risk of malignant transformation of oral leukoplakia, such as age, gender, tobacco habits, homogeneity, and size of the lesion, oral subsite, degree of epithelial dysplasia, if present, loss of heterozygosity, survivin, matrix metalloproteinase 9, and DNA content. ,,] These lesions often are associated with carcinogenic exposures, such as from use of tobacco and alcohol , ; however, the etiology of oral leukoplakia is not fully understood. The level of risk for malignant transformation of leukoplakia is associated with lesion histology. The frequency of leukoplakia is highly variable among geographic areas and demographic groups. The overall malignant transformation rates for dysplastic lesions range from 11% to 36%, depending on the length of follow-up.  A recent report showed that proliferative verrucous leukoplakia has a malignant transformation rate as high as 70.3% (mean follow-up of 11.6 years). 
This fact has been established that cytochrome P4502E1 enzymes are involved in the phase I of metabolism of xenobiotic compounds catalyzing the addition of an atom of molecular oxygen to lipophilic toxic compounds. This addition converts them into more hydrophilic compounds helping in easy excretion.  CYP2E1 is a drug-metabolizing enzyme, responsible for the metabolism of various xenobiotics. CYP2E1 is expressed in cultured human oral epithelial cell.
Investigation of the association between cancer development risk and CYP2E1 gene polymorphism is of significant interest, because this enzyme is involved in metabolism of aniline, vinyl chloride, and urethane and participates in the activation of N-nitrosodimethylamine, 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone, and nicotine-dependent N-nitrosonornicotine. ,,,, All these compounds initiate malignancies of various localizations, including stomach, esophagus, liver, and lung.  CYP2E1 catalytic activity was found to display individual differences, which can lead to increased risks of tumor development. Changes in enzymatic activity may be a consequence of genetic polymorphism or gene induction by xenobiotics. Indeed, a correlation was found between mRNA level, CYP2E1 catalytic activity, and transcriptional activity of polymorphic gene variants. The CYP2E1 gene is present in the population in various polymorphic forms. Polymorphisms detectable by DraI and Taq I digestion are not thought to affect transcription or function of the enzyme coded for by the gene. In contrast, the variant detectable by RsaI digestion (called the c2 variant) contains polymorphic base substitution sites in a region of the gene that is not transcribed but that appears to be involved in the transcriptional regulation of CYP2E1 expression.
It is also demonstrated that CYP2E1 synthesis and catalytic activity levels are changed under exposure to environmental factors. This can result in the development of acquired susceptibility to diseases. This study discusses the association of CYP2E1 polymorphism with individual human susceptibility to leukoplakia than transformation to malignancies.
| » Materials and Methods|| |
In the current study, a total of 105 leukoplakia patients were genotyped for CYP2E1 polymorphism (93 males and 12 females; mean age ± SD: 47.5 ± 10.6). Ninety-six unrelated healthy controls (85 males and 11 females; mean age ± SD: 49 ± 11.1) were included in this study. An informed consent was obtained from all the participants and the study was approved by the institutional ethical committee. Patients were those who enrolled in Dental College, King George Medical University (K.G.M.U.), Lucknow, India. All the patients had either reported for treatment of leukoplakia or were diagnosed with leukoplakia during routine oral examination. Individuals with a positive history of intake of tobacco in any form, presence of fibrous bands in the labial and/or buccal mucosa, and inability to open mouth were diagnosed with leukoplakia. The inclusion criteria for the controls was absence of a prior history of cancer or any other oral lesion.
Human CYP2E1 gene is located on the 10 th chromosome, consists of 9 exons and 8 introns, contains a typical TATA-box and occupies 11413-bp of genomic DNA.  CYP2E1 is constituently expressed primarily in the liver. 
PstI and RsaI polymorphism
These polymorphisms were screened by PCR-RFLP analysis method using primers flanking the RsaI (−1293G > C) and PstI (−1053C > T) polymorphic site in the 5′ regulatory region located upstream of the CYP2E1 transcriptional start site.  A 410-bp fragment was generated by PCR in a 20 μL reaction volume containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl 2 200 μM of dNTPs, 6 pmol of each of the primers, 100-200 ng of genomic DNA, and one unit Fast Start Taq DNA polymerase. The PCR products (410-bp) were divided and separately subjected to PstI and RsaI restriction enzyme digestions. The digested samples were then analyzed by electrophoresis in a 2% agarose gel. The presence of restriction site on both chromosomes yielded to fragments of 120- and 290-bp for the PstI and 360- and 50-bp for the RsaI digested.
The CYP2E1 DraI (7632T > A) polymorphism was screened by PCR-RFLP analysis method using primers located in the intron six region of the CYP2E1 gene.  A 373-bp fragment was generated by PCR in a 10 μL reaction volume containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl 2 200 μM of dNTPs, 2.5 pmol of each of the primers, 50-100 ng of genomic DNA, and 0.5 unit Fast Start Taq DNA polymerase. The amplified DNA (373-bp) was digested with the DraI restriction endonuclease subjected to electrophoresis in a 2% agarose gel. In this analysis, the presence of an undigested 373-bp fragment (due to the absence of a restriction site on both chromosomes) and the presence of digested fragments of sizes 240- and 133-bp (due to restriction site on both chromosomes) were indicative of the CC and CD genotypes, respectively. The presence of 373-, 240-, and 133-bp DNA fragments identified the CD genotypes.
The significance of this study was evaluated by Chi-square or Fisher's exact test. Odds ratio (OR) was calculated as an estimate of relative risk of having disease according to the relative frequency of different genotypes among the cases as well as the controls (adjusting for age and gender). Crude ORs and 95% confidence intervals (95% CIs) were calculated for CYP2E1. P value was considered significant at <0.05. All statistical tests were performed using Statistical Package for the Social Sciences (SPSS version 12) software.
| » Results|| |
A total of 105 leukoplakia patients and 96 controls were included in the study [Table 1]. The mean age of leukoplakia patients and control were 47 ± 10 and 51 ± 10 years, respectively. Individuals in the study population were divided into three different tobacco habit groups: smokers, smokeless, tobacco users (chewers/dipper), and those with mixed habits. The exclusive smokers comprised 62 (59%) leukoplakia patients and 53 (53%) controls. The exclusive smokeless tobacco users were 16 (15%) among the leukoplakia patients and 27 (28%) among the controls, whereas 27 (26%) leukoplakia patients and 16 (17%) controls had both the types (smoking and smokeless) of tobacco habits simultaneously. To increase the number of individuals in tobacco smoking habit group, exclusive smokers and those with mixed habits were pooled as total smokers in leukoplakia and control groups [89 (84%) and 69 (72%) in the respective groups].
|Table 1: Distribution of demographic variables for patients and controls|
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The range of lifetime smoking exposure in leukoplakia and controls were (5-80 PY in both groups), but the mean smoking exposure in both the groups were (leukoplakia: 28 ± 21.8 PY, control: 27 ± 17 PY). The range of lifetime smokeless tobacco exposures (i.e., CY) were similar in both leukoplakia and controls (10-450 CY in [Table 1]). But the mean smokeless tobacco dose in two groups were (leukoplakia: 150 ± 175 CY, controls: 137 ± 110 CY). The smokers of both the patients and controls were classified as light and heavy smokers. It was shown in [Table 1].
Because the frequency of variant CYP2E1 (CC) genotype were low in the patients and control population, (CC) and (CD) genotype were pooled and compared. The frequency of variants homozygous and heterozygous CYP2E1 (CC + CD) genotypes, at DraI in leukoplakia patients and control population was not significantly different (age, gender, and tobacco habits-adjusted OR = 1.4, 95% CI = 0.7-2.5). No statistically significant difference was observed when frequencies of (CC + CD) genotypes among exclusive smokers/smokeless tobacco users, mixed habitual, and total smokers/smokeless tobacco users of leukoplakia patients and control were compared. But the frequencies of CC + CD genotypes was significant when light smokers (<23 PY) of leukoplakia patients and controls (OR = 3; 95%, CI = 1.0-9.0) were compared. But for the other does of smoking and smokeless tobacco, no significant difference in the distribution of CYP2E1 (CC + CD) genotypes were observed among the leukoplakia patients and the controls [Table 2] and [Figure 1].
|Figure 1: CYP2E1 DraI polymorphism. Lane M, DNA marker (ö X174 digested with HaeIII restriction enzyme), lanes 1 - 4 correspond to D/D homozygotes, lanes 5 - 8 correspond to CID heterozygotes, and lanes 9 - 12 correspond to C/Cd to homozygotes|
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|Table 2: Distribution of CYP2E1 (CC+CD) genotypes at DraI site among leukoplakia patients and control individuals|
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The frequencies of heterozygous and homozygous genotypes (c1/c2 + c2/c2) at CYP2E1 were very low and similar in patient and control populations (3% and 1%, respectively; shown in [Table 3] and [Figure 2] and [Figure 3]). So the distribution of these genotypes could not be compared among the patients and controls according to the different types of tobacco habits and doses. No significant difference in distribution of c1/c2 + c2/c2 genotypes at CYP2E1 was observed (age, gender, PY, and CY adjusted OR = 2.8; 95% CI 0.3-71.0) between the leukoplakia patients and the controls.
|Figure 2: CYP2E1 PstI polymorphism. Lane M, DNA marker (ö X174 digested with HaeIII restriction enzyme), lanes 1 - 6 correspond to PstI undigested homozygous (410-bp DNA fragments), lanes 7 - 12 correspond to PstI undigested homozygous (410-, 290-, and 120-bp DNA fragments), homozygous were absent in study population|
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|Figure 3: CYP2E1 RsaI polymorphism. Lane M, DNA marker (ö X174 digested with HaeIII restriction enzyme), lanes 1 - 6 corresponds to RsaI digested homozygous (410-bp DNA fragments), lanes 7 - 12 correspond to RsaI digested heterozygous (360-, 290-, and 50-bp DNA fragments), undigested homozygotes were absent in study population|
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|Table 3: Distribution of combined CYP2E1 (c1/c2+c2/c2) genotypes among the leukoplakia patients and control individuals|
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| » Discussion|| |
Epidemiologic studies have strongly implicated smoking and smokeless tobacco use as etiologic agents in the development of oral leukoplakia in different populations worldwide.  The cytochrome P450 enzymes are the large multigene family and are important in phase I activation reactions to convert procarcinogens present in tobacco into carcinogens. The combination of reactive intermediates, formed in Phase I reaction, with an electron-deficient DNA vase-like guanine forms DNA adducts. The DNA adducts can damage DNA structure, which in turn can lead to the formation of mutants when the DNA replicates. An increase of risk of lung, bladder, esophageal cancers, and cancers in the oral cavity has been reported in tobacco users (IARC, 1985, 1986). In this study we examined the association between polymorphisms in CYP2E1 gene and the risk of oral leukoplakia among north Indian tobacco users. The patients and control subjects of the study were recruited from King George Medical University, Lucknow, so all patients and control subjects have similarity in ethnicity.
In this study, ranges in lifetime smokeless and smoking tobacco exposure were similar (in patients and control subjects shown in [Table 1]). Mean smoking exposure in leukoplakia and control individual were 28 PY and 27 PY, respectively. Mean smokeless tobacco exposure in leukoplakia patients (150 CY) was higher than that of the control subjects (137 CY). These controls were disease-free and had tobacco exposure, so they served as good controls.
The male-to-female ratios were approximately similar in both the leukoplakia patients and the controls (8:1). Incidences of oral leukoplakia were more in the men than in the women because of gender difference in tobacco habits. A silent feature of this study, however, is that it has examined the association between risk of oral leukoplakia and different CYP2E1 genotypes in the presence of different types of tobacco habits using satisfactory measurements of exposure.
At the DraI site, the combined CC + CD genotypes (i.e., expected risk-genotypes) did not modulate the risk of the diseases when all patients and controls were compared. This finding is consistent with reports on Japanese and Caucasians but is in contrast with a report on upper aerodigestive tract in Caucasians.  The patients and controls was stratified according to the different kinds and doses of tobacco habit. But the combined rare and heterozygous (CC + CD) genotypes increased the risk of leukoplakia among light smokers (<23 PY), data shown in [Table 2]-An observation also noticed with lung and oral cancer patients. , Such a high effect of low-dose tobacco habits had been explained by individual's susceptibility and formation of higher DNA carcinogens adduct due to polymorphism in some metabolic genes (e.g., GST, CYP2E1).  So attributable risk should be accessed in a larger case-control study, exposed to low tobacco dose. The apparent absence of risk of leukoplakia in heavy tobacco users may be due to the overwhelming effect of heavy tobacco dose on these genotypes or due to the effect of small sample size being reduced due to the stratification of the samples. The lack of association at high tobacco dose also suggests that study of polymorphism in other metabolic and/or DNA repair genes may provide important finding to explain this phenomenon.
We did not observe the association between genotype at the PstI-RsaI sites of CYP2E1and the risk of leukoplakia on this population [Table 3]. But polymorphism at these sites modulated the risk of cancer in Chinese,  Caucasian, and African-American population.  This difference in observation between this part of Indian population and other populations may be because variant c1 allele at PstI and RsaI sites is very less frequent in this population and alcohol drinkers are few in this population compared with Chinese and Caucasian populations. So this may be one of the reasons for which we could not detect the effect of this variant allele in this part of Indian population.
In this context, nitrosamines should be considered as important carcinogens because some of the nitrosamines are activated primarily by CYP2E1 enzymes. In addition to activation of nitrosamines, PAH and HAA (heterocyclic amines) are also activated by CYP2E1 enzymes. Apart from these, CYP2E1 may also catalyze the oxidation and DNA adducts formation of low molecular weight carcinogens and increases the production of reactive oxygen species that may cause DNA damage. The CYP2E1 is a major enzyme that is involved in the α-hydroxylation of low molecular nitrosamines present in tobacco to yield compounds that are able to react with DNA at a number of different sites in a manner typical of alkylating agents. Some of the resulting adducts (e.g., O 6 -methylguanine) are mutagenic and cause GC/AT transition mutation. So this knowledge and the present study finding indicate the biological plausibility that the rare "C" allele of CYP2E1 may be a risk factor for leukoplakia. Because the rare "C" allele is associated with enhanced transcription of the CYP2E1 genes,  more toxic products may have been synthesized to cause leukoplakia in these patients. How this rare "C" in intron 6 affects the activity of the CYP2E1 enzyme in vivo remains to be determined. The CYP2E1 enzyme is not only involved in metabolic activation of the nitrosamines of tobacco but also in that of alcohol to produce reactive free radicals that may initiate lipid peroxidation and subsequently carcinogenesis.  All patients of this study had tobacco smoking and/or smokeless tobacco habits, but only few of them (<5%) had occasional drinking habit. Probably this has limited our observation on association between risks of leukoplakia and CC + CD genotypes only in low smoking patients. But the study with large number of samples will provide better understanding of the risk of leukoplakia in relation to CYP2E1 polymorphism.
The result indicates that the rare C allele at the DraI polymorphic site of gene may enhance susceptibility to leukoplakia among tobacco users in the population. Finally, the study with large numbers of samples will provide better understanding of the risk of leukoplakia in relation to CYP2E1 polymorphism.
| » Conclusion|| |
In conclusion, our results demonstrate an association between CYP2E1 genetic polymorphism and leukoplakia risk, premalignant lesion. Results from our study indicate that the CYP2E1 polymorphism, singly showed a protection toward the oral leukoplakia. Independent confirmation of this finding is required, and additional examination of the joint effect of CYP2E1 genotype and other non-tobacco-related exposures is needed before more conclusive interpretation of our results can be made. This study demonstrates the importance of genetic variations in CYP2E1genes in susceptibility toward oral leukoplakia and it is conceivable that these variants will interact with environmental carcinogens and possibly some combinations of these genotypes will be at a high risk to oral leukoplakia.
| » Acknowledgment|| |
The authors thank Dr. R. R. Paul and Dr. Bidyut Roy for their useful guidance and reading the manuscript. This research is supported in part by R. Ahmad Dental College and Hospital, Kolkata, and Biological Sciences Division, Indian Statistical Institute, Kolkata.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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