Open Access

Role of CYP2E1 genotypes in susceptibility to colorectal cancer in the Kashmiri population

  • A. Syed Sameer1,
  • Saniya Nissar1,
  • Qurteeba Qadri1,
  • Shafia Alam1,
  • Shahid Mudasir Baba1 and
  • Mushtaq A. Siddiqi1Email author
Human Genomics20115:530

https://doi.org/10.1186/1479-7364-5-6-530

Received: 31 January 2011

Accepted: 31 January 2011

Published: 1 October 2011

Abstract

Cytochrome P450 2E1 (CYP2E1) is a key enzyme involved in the metabolic activation of procarcinogens such as N-nitrosoamines and low-molecular-weight organic compounds. The main aim of this study was to determine whether CYP450 2E1 polymorphisms are associated with the risk of colorectal cancer (CRC). We investigated the genotype distribution of the CYP2E1 gene RsaI and a 96-base pair (bp) insertion in 86 CRC cases in comparison with 160 healthy subjects. We found the frequency of the CYP2E1 RsaI genotype to be 53.5 per cent (46/86) for c1/c1, 17.4 per cent (15/86) for c1/c2 and 29.1 per cent (25/86) for c2/c2, and the CYP2E1 98-bp insertion frequencies to be 63.9 per cent (55/86) for non-insertion (i/i), 22.1 per cent (19/86) for heterozygous insertion (i/I) and 36.0 per cent (12/86) for homozygous insertion (I/I) among CRC cases. We also found the CYP2E1 RsaI c2/c2 and CYP2E1 98-bp heterozygous i/I genotypes to be significantly associated with an increased risk of CRC (p = 0.01). We suggest that CYP2E1 polymorphisms are involved in the susceptibility to developing CRC in the ethnic Kashmiri population.

Keywords

colorectal cancerCYP2EpolymorphismKashmir

Introduction

Colorectal cancer (CRC) is one of the major causes of mortality and morbidity, and is the fourth most common cancer in men and the third most common cancer in women worldwide [1]. Kashmir has been reported as being a high-incidence area for gastrointestinal (GIT) cancers [2, 3]. In the Kashmir valley, CRC represents the third most common GIT cancer after oesophageal and gastric cancers [46].

Epidemiological studies on various populations have shown that an increased risk of developing GIT cancers is associated with diet [2, 7, 8]. One important hypothesis that has received a large amount of attention is that N-nitroso compounds from dietary sources are involved in the carcinogenesis of GIT cancer [9, 10]. It is known that most exogenous (xenobiotics) and endogenous chemical carcinogens require biotransformation to activated forms to be carcinogenic [11, 12]. Most of the enzymes involved in drug metabolism are genetically polymorphic, and these polymorphisms may affect enzyme activity or inducibility [1315].

The cytochrome P450 2E1 gene (CYP2E1) is located on chromosome 10q26.3. It is 18,754 base pairs (bp) long, consists of nine exons and eight introns and encodes a 493-amino acid protein. CYP2E1 belongs to the cytochrome P450 superfamily [16]. It is a natural ethanol-inducible enzyme and is of great interest because of its role in the metabolism and bioactivation of many low molecular weight compounds, including ethanol and acetone, drugs such as acetaminophen, isoniazid, chlorzoxazone and fluorinated anaesthetics and many procarcinogens such as benzene, N-nitrosoamines, vinyl chloride and styrene [1720].

CYP2E1 contains six restriction fragment length polymorphisms, of which the RsaI polymorphism (CYP2E1*5B; C-1054T substitution) and the 96-bp insertion in its 5'-flanking region have drawn much interest [16, 20, 21]. The RsaI polymorphism has been shown to affect the transcriptional level of the gene. The variant type of this polymorphic site can enhance the transcription and increase the level of CYP2E1 enzymatic activity in vitro [22]. The variant allele of the 96-bp insertion polymorphism has been shown to express greater transcriptional activity [23].

We carried out a case-control study in our population to determine if these CYP2E1 polymorphisms are associated with an altered risk of developing CRC. We also investigated whether there was a link between the clinicopathological variables and the CYP2E1 genotype, and hence their role in CRC predisposition.

Materials and methods

Study population

This study included 86 CRC cases. All patients were recruited from the Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Kashmir. Blood samples were collected from 160 age- and sex-matched individuals with no signs of any cardiac disease, to serve as external controls. The mean age of both patient and control groups was 52 years (see Table 1 for details).
Table 1

Frequency distribution analysis of selected demographic and risk factors in colorectal cancer cases and controls

Variable

Cases

(n= 86)

Controls

(n= 160)

pValue

Age group

   

≤ 50

30 (34.9%)

56 (35.0%)

1

> 50

56 (65.1%)

104 (65.0%)

 

Gender

   

Female

37 (43.0%)

72 (45.0%)

0.764177

Male

49 (67.0%)

88 (55.0%)

 

Dwelling

   

Rural

59 (68.6%)

104 (65.0%)

0.565659

Urban

27 (31.4%)

56 (35.0%)

 

Smoking status

   

Never

31 (36.0%)

75 (46.8%)

0.102256

Ever

55 (64.0%)

85 (53.2%)

 

Pesticide exposure

   

Never

33 (38.4%)

75 (46.8%)

0.200325

Ever

53 (61.6%)

85 (53.2%)

 

Data on all CRC patients were obtained from personal interviews with patients and/or their guardians, and their medical records. All patients and/or guardians were informed about the study and their willingness to participate was recorded on a predesigned questionnaire (available on request). The collection and use of blood samples (from patients and controls) for this study had been previously approved by the appropriate institutional ethics committee.

DNA extraction and polymerase chain reaction

DNA extraction was performed using the ammonium precipitation method. Genotyping for the CYP2E1 RsaI and 96-bp insertion polymorphisms was determined by the method described by Morita et al. [21]. The oligonucleotide primers used for the amplification of the target regions are listed in Table 2. The polymerase chain reaction (PCR) was carried out in a final volume of 25 μl, containing 50 ng genomic DNA template, 1× PCR buffer (Fermentas, Glen Burnie, MD), with 2 mM MgCl2, 0.4 μM of each primer (GenScript, Piscataway, NJ), 50 μM deoxynucleotide triphosphates (dNTPs) (Fermentas) and 0.5 U DNA polymerase (Fermentas). For PCR amplification, the standard programme was used as follows: one initial denaturation step at 94°C for 7 minutes, followed by 30 denaturation cycles of 30 seconds at 94°C, 45 seconds of annealing at X°C (See Table 2) and 45 seconds of extension at 72°C for 35 cycles, followed by a final elongation cycle at 72°C for 7 minutes.
Table 2

Primers for CYP2E1 gene polymorphism

Target codon

Sequence

Amplicon (bp)

Tm (°C)

CYP2E1 * 5B

F5'-CCAGTCGAGTCTACATTGTCA-3'

413 bp

55

RsaI

R5'-TTCATTCTGTCTTCTAACTGG-3'

  

CYP2E1

F5'-GTGATGGAAGCCTGAAGAACA-3'

729 bp for insertion

66

96-bp insertion

R5'-CTTTGGTGGGGTGAGAACAG-3'

633 bp for non-insertion

 

Tm, melting temperature.

The PCR product of CYP2E1 RsaI was 413 bp in length and was then digested with 2 U RsaI in a reaction mixture of 20 μl for 3 hours at 37°C.

The digestion resulted in fragments of 352 bp and 61 bp for the c1 allele. The PCR product of the CYP2E1 96-bp insertion allele was 729 bp in length and that of the non-insertion allele was 633 bp in length.

DNA amplicons, as well as the digestion products, were electrophoresed through a 2-3 per cent agarose gel (Genie, Bangalore, India) for resolution. The genotypes of > 20 per cent of the samples were reassessed in a double-blind manner by two independent researchers, to confirm the results. A positive control for each polymorphism was used for 50 per cent of the samples.

Statistical analysis

The observed frequencies of the above genotypes in patients with CRC were compared with controls using chi-square or Fisher exact tests when the expected frequencies were small. The chi-square test was used to verify whether the genotype distributions were in Hardy-Weinberg equilibrium. Statistical significance was set at p ≤ 0.05. Statistical analyses were performed using PASW version 18 software.

Results

A total of 86 CRC cases and 160 control subjects were included in this study. The patients comprised 49 males and 37 females (M/F ratio = 1.32) and the control subjects consisted of 88 males and 72 females (M/F ratio = 1.2). The mean age in patient and control groups was 52 years. No significant gender- or age-related differences were observed between the groups (p > 0.05). Furthermore, of 86 confirmed cases of CRC, 81 were sporadic, four were familial adenomatous polyposis and one case was hereditary non-polyposis (Lynch Syndrome) CRC. All but one case had an adenocarcinoma, one had squamous cell carcinoma of the basal cell type. Thirty-six patients had carcinoma in the colon and 50 carcinoma in the rectum. Fifty-nine were rural-and 27 urban-living, and 55 were smokers and 31 non-smokers (see Table 1 for further details).

Among the CRC cases, we found the frequency of the CYP2E1 RsaI genotype to be 53.5 per cent (46/86) for c1/c1, 17.4 per cent (15/86) for c1/c2 and 29.1 per cent (25/86) for c2/c2, while the frequency in the general control population was 70.0 per cent (112/160) for c1/c1, 12.5 per cent (20/160) for c1/c2 and 17.5 per cent (28/160) for c2/c2. The association between the CYP2E1 RsaI polymorphism and the CRC cases was found to be significant (p < 0.05) (Table 3). Furthermore, for the 96-bp insertion polymorphism of CYP2E1, the genotype frequencies were 63.9 per cent (55/86) for non-insertion (i/i), 22.1 per cent (19/86) for the heterozygous insertion (i/I) and 13.9 per cent (12/86) for the homozygous insertion (I/I), while in the general control population the frequency of i/i was found to be 81.3 per cent (130/160), 7.5 per cent (12/160) for i/I and 11.3 per cent (18/160) I/I. The association of the CYP2E1 98-bp insertion polymorphism with the CRC cases was also found to be significant (p < 0.05) (Table 3). In individual patients it was found that the CYP2E1 RsaI c2/c2 and CYP2E1 96-bp heterozygous i/I genotypes were both associated with an increased risk of CRC (p = 0.01 and 0.0009, respectively).
Table 3

Genotype frequencies of CYP2E1 polymorphism in cases and controls

CYP2E1genotype

Cases

(n= 86)

Controls

(n= 160)

OR (95% CI); χ2a; pvalueb

χ2; pvalue

(overall)

RsaI

    

c1/c1 (wild-type)

46 (53.5%)

112 (70.0%)

1.0 (ref)

6.81; 0.03

c1/c2

15 (17.4%)

20 (12.5%)

1.8 (0.86-3.87); 0.11; 0.15

 

c2/c2 (variant)

25 (29.1%)

28 (17.5%)

2.17 (1.14-4.11); 0.01; 0.01

 

c1/c2 or c2/c2

40 (46.5%)

48 (30.0%)

2.02 (1.17-3.48); 0.009; 0.01

 

96-bp insertion

    

i/i (non-insertion)

55 (63.9%)

130 (81.3%)

1.0 (ref)

12.1; 0.002

i/I

19 (22.1%)

12 (7.5%)

3.74 (1.7-8.23); 0.0006; 0.0009

 

I/I (insertion)

12 (13.9%)

18 (11.3%)

1.57 (0.79-3.49); 0.25; 0.29

 

i/I or I/I

31 (36.0%)

30 (18.8%)

2.44 (1.31-4.41); 0.003; 0.003

 

a Pearson value; bFisher exact value. Significant p values are shown in bold.

Analysis of the CYP2E1 RsaI and 98-bp insertion polymorphisms with that of the clinicopathological parameters also revealed significant associations with many parameters (Tables 4 and 5). The CYP2E1 RsaI c2/c2 genotype was associated significantly (p < 0.05) with age, nodal status (Table 4) and tumour grade, and the CYP2E1 96-bp i/I genotype was associated significantly (p < 0.05) with tumour location (Table 5).
Table 4

Association between CYP2E1 (RsaI) polymorphism and clinicopathological characteristics

Variables

  

Cases (n= 86)

  
 

n= 86

c1/c1

46 (53.5%)

c1/c2

15 (17.4%)

c2/c2

25 (29.1%)

χ2; pvalue

Age group

     

≤ 50

30 (34.9%)

21

5

4

6.29; 0.04

> 50

56 (65.1%)

25

10

21

 

Gender

     

Female

37 (43.0%)

20

6

11

0.07; 0.96

Male

49 (67.0%)

26

9

14

 

Dwelling

     

Rural

59 (68.6%)

27

11

21

5.0; 0.08

Urban

27 (31.4%)

19

4

4

 

Smoking status

     

Ever

55 (64.0%)

29

8

18

1.45; 0.48

Never

31 (36.0%)

17

7

7

 

Tumour location

     

Colon

36 (41.9%)

19

5

12

0.84; 0.65

Rectum

50 (58.1%)

27

10

13

 

Nodal status

     

Involved

48 (55.8%)

24

4

20

11.34; 0.003

Not Involved

38 (44.2%)

22

11

5

 

Tumour grade

     

A + B

38 (44.2%)

22

11

5

11.34; 0.003

C + D

48 (55.8%)

24

4

20

 

Pesticide exposure

     

Ever

53 (61.6%)

26

8

19

3.13; 0.20

Never

33 (38.4%)

20

7

6

 

Bleeding PR/constipation

     

Yes

60 (69.8%)

32

10

18

0.13; 0.93

No

26 (30.2%)

14

5

7

 

Tumour type a

     

Mucinous

33 (38.5%)

20

6

7

1.84; 0.39

Non-mucinous

52 (60.5%)

25

9

18

 

a One was squamous cell carcinoma. Significant p values are shown in bold.

Table 5

Association between CYP2E1 (96 bp) polymorphism and clinicopathological characteristics

Variables

  

Cases (n= 86)

  
 

n= 86

i/i 55 (63.9%)

i/I 19 (22.1%)

I/I 12 (13.9%)

χ2; pvalue

Age group

     

≤ 50

30 (34.9%)

19

7

4

0.05; 0.97

> 50

56 (65.1%)

36

12

8

 

Gender

     

Female

37 (43.0%)

26

8

3

2.0; 0.36

Male

49 (67.0%)

29

11

9

 

Dwelling

     

Rural

59 (68.6%)

38

13

8

0.03; 0.98

Urban

27 (31.4%)

17

6

4

 

Smoking status

     

Ever

55 (64.0%)

35

10

10

3.01; 0.22

Never

31 (36.0%)

20

9

2

 

Tumour location

     

Colon

36 (41.9%)

22

5

9

7.38; 0.02

Rectum

50 (58.1%)

33

14

3

 

Nodal status

     

Involved

48 (55.8%)

28

12

8

1.53; 0.46

Not Involved

38 (44.2%)

27

7

4

 

Tumour grade

     

A + B

38 (44.2%)

27

7

4

1.53; 0.46

C + D

48 (55.8%)

28

12

8

 

Pesticide exposure

     

Ever

53 (61.6%)

38

9

6

3.62; 0.16

Never

33 (38.4%)

17

10

6

 

Bleeding PR/constipation

     

Yes

60 (69.8%)

42

11

7

3.15; 0.20

No

26 (30.2%)

13

8

5

 

Tumour type*

     

Mucinous

33 (38.5%)

22

7

4

0.27; 0.87

Non-mucinous

52 (60.5%)

32

12

8

 

*One was squamous cell carcinoma. Significant p values are shown in bold.

Discussion

As reported previously in various studies on the Kashmiri population,[2, 4, 5] it has been proven beyond doubt that this population is exposed to a special set of environmental and dietary risks, including exposure to nitroso compounds, amines and nitrates, reported to be present in local foodstuffs, most of which have been shown to contain important irritants and carcinogens [3, 6].

In the present study, we assessed the two most common single nucleotide polymorphisms of CYP2E1, RsaI and the 96-bp insertion, in an ethnic Kashmiri population for the first time, as the role of these polymorphisms in relation to the risk of CRC has not been reported from this part of the world.

Although a number of studies have been carried out around the world on the association between the CYP2E1 polymorphism and cancer risk, the findings have been inconsistent [24]. Some studies demonstrated that the common genotype or alleles (i.e. RsaI and the 96-bp insertion) confer a greater risk of oral and pharyngeal,[25] oesophageal,[26] liver [27] and lung [28] cancers. In other studies, however, an increased risk of oral,[29] nasopharyngeal,[30] liver [31] and colorectal [32, 33] cancers was observed with the rare genotype or allele carriers (i.e. the variant form of these two genotypes).

In the present study, we found the frequency of the CYP2E1 RsaI genotype to be 53.5 per cent (46/86) for c1/c1, 17.4 per cent (15/86) for c1/c2 and 29.1 per cent (25/86) for c2/c2 among CRC cases, and the CYP2E1 RsaI polymorphism to be significantly associated with the risk of CRC (p < 0.05). The overall risk of CRC was found to be 2.17 times higher in case of c2/c2 homozygous state. These results were consistent with those of Kiss et al. [32] and Yu et al. [33] Kiss et al. found the CYP2E1 c2 allele to be significantly associated with CRC (odds ratio 1.91, 95 per cent confidence interval 1.05-3.52) in a Hungarian population [32]. Yu et al. found the CYP2E1 c2 allele to be a susceptibility factor for CRC [33]. This may be because of the increased transcriptional activation of the c2 variant of the CYP2E1 gene, with elevated expression levels of CYP2E1 mRNA and protein [34]. We also found a significant association between the CYP2E1 RsaI genotype and age (> 50), nodal status (involved) and tumour grade (C + D). Furthermore, a recent meta-analysis by Zhou et al. also revealed the CYP2EI RsaI c2/c2 genotype to be associated with an increased risk of CRC [20].

In the case of the 98-bp insertion polymorphism, we found that the genotype frequencies were 63.9 per cent (55/86) for non-insertion (i/i), 22.1 per cent (19/86) for heterozygous (i/I) and 36.0 per cent (12/86) in case of homozygous insertion (I/I) among CRC (86) cases and heterozygous i/I genotype to be associated with increased risk of CRC (p = 0.0009). The overall risk of CRC was found to be 3.74 times higher in the case of the i/I heterozygous state. These results are different from those found in a previous study on CRC;[21] however, the present study is only the third such study on this polymorphism to have been carried out. The other study in this field examined the relationship between the 96-bp insertion polymorphism and cancer risk, and was carried out in Japan by Itoga et al.,[35] who found an increased risk of oesophageal cancer, but not of lung cancer, in individuals who had two variant 96-bp insertion alleles.

We also found a significant association between the CYP2E1 i/I heterozygous genotype and the tumour location (rectum). This finding was in line with that of a case-control study carried out in Hawaii, where the authors showed an increased risk of CRC, especially of rectal cancer, in those having at least one 96-bp insertion [36]. This was hypothesised to be because of a high intake of red meat, which increases the endogenous production of N-nitroso compounds in the intestine. The Kashmiri population is also known to consume high quantities of red meat.

Furthermore, it has been found that both the RsaI c2 and 96-bp I alleles are fairly common in Asian populations compared with Caucasians. In the present study, we found the frequencies of RsaI c2 and 96-bp I alleles to be of 30.0 per cent and 18.8 per cent, respectively (see Table 3). These frequencies are similar to those found for these alleles in other Asian populations. The frequencies of the RsaI c2 allele were 22 per cent in Japanese,[21] 4 per cent in Caucasians [36] and 15 per cent in Hawaiians [36]. The frequencies of the 96-bp insertion allele were 23 per cent in Japanese,[21] 15 per cent in Taiwanese,[37] 10 per cent in African-American,[37] and 2 per cent in Caucasian [37] subjects.

Conclusion

We conclude that there is a significant relationship between the CYP2E1 RsaI and 96-bp insertion polymorphisms and the risk of CRC in the ethnic Kashmiri population. We also observed a significant correlation between the RsaI c2/c2 variant and 96-bp i/I heterozygous genotype with various clinicopathological variables in this population. These correlations now need to be authenticated in a large sample study, in order to discern racial differences and determine the aggressiveness of CRC.

Declarations

Acknowledgements

The authors gratefully acknowledge the financial support provided by the Sher-I-Kashmir Institute of Medical Sciences, Kashmir, for this work. We also thank the head and technical staff of the operating theatre in the Department of General Surgery at the Institute who helped us with tissue procurement, and the anonymous pathologists at the Department of Pathology also at the Sher-I-Kashmir Institute of Medical Sciences for the histopathological assessment of the tumour tissues.

Authors’ Affiliations

(1)
Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura

References

  1. Center MM, Jemal A, Ward E: International trends in colorectal cancer incidence rates. Cancer Epidemiol Biomarkers Prev. 2009, 18: 1688-1694. 10.1158/1055-9965.EPI-09-0090.View ArticlePubMedGoogle Scholar
  2. Mir MM, Dar NA, Gochhait S, Zargar SA, et al: p53 mutation profile of squamous cell carcinomas of the esophagus in Kashmir (India): A high-incidence area. Int J Cancer. 2005, 116: 62-68. 10.1002/ijc.21002.View ArticlePubMedGoogle Scholar
  3. Murtaza I, Mushtaq D, Margoob MA, Dutt A, et al: A study on p53 gene alterations in esophageal squamous cell carcinoma and their correlation to common dietary risk factors among population of the Kashmir valley. World J Gastroenterol. 2006, 12: 4033-4037.PubMed CentralPubMedGoogle Scholar
  4. Sameer AS, Rehman S, Pandith AA, Syeed N, et al: Molecular gate keepers succumb to gene aberrations in colorectal cancer in Kashmiri population, revealing a high incidence area. Saudi J Gastroenterol. 2009, 15: 244-252. 10.4103/1319-3767.56102.PubMed CentralView ArticlePubMedGoogle Scholar
  5. Sameer AS, Chowdri NA, Syeed N, Banday M, et al: SMAD4 -- Molecular gladiator of the TGF-beta signaling is trampled upon by mutational insufficiency in colorectal carcinoma of Kashmiri population: An analysis with relation to KRAS proto-oncogene. BMC Cancer. 2010, 10: 300-10.1186/1471-2407-10-300.PubMed CentralView ArticlePubMedGoogle Scholar
  6. Siddiqi M, Kumar R, Fazili Z, Spiegelhalder B, et al: Increased exposure to dietary amines and nitrate in a population at high risk of esophageal and gastric cancer in Kashmir (India). Carcinogenesis. 1992, 13: 1331-1335. 10.1093/carcin/13.8.1331.View ArticlePubMedGoogle Scholar
  7. Ji BT, Chow WH, Yang G, Mclaughlin JK, et al: Dietary habits and stomach cancer in Shanghai, China. Int J Cancer. 1998, 76: 659-664. 10.1002/(SICI)1097-0215(19980529)76:5<659::AID-IJC8>3.0.CO;2-P.View ArticlePubMedGoogle Scholar
  8. Hill MH: Nutritional and metabolic aspects of gastrointestinal cancer. Curr Opin Clin Nutr Metab Care. 1998, 1: 405-407. 10.1097/00075197-199809000-00006.View ArticlePubMedGoogle Scholar
  9. Deng DJ, Chang Y, Li J: Comparison of total N-nitrosamides in fasting gastric juice from subjects in high and low risk areas for gastric cancer. Zhonghua Zhong Liu Za Zhi. 1997, 19: 96-99.PubMedGoogle Scholar
  10. Ward MH, Lopez-Carrillo L: Dietary factors and the risk of gastric cancer in Mexico City. Am J Epidemiol. 1999, 149: 925-932. 10.1093/oxfordjournals.aje.a009736.View ArticlePubMedGoogle Scholar
  11. Kim JW, Lee CG, Park YG, Kim KS, et al: Combined analysis of germline polymorphisms of P53, GSTM1, GSTT1, CYP1A1, and CYP2E1. Cancer. 2000, 88: 2082-2091. 10.1002/(SICI)1097-0142(20000501)88:9<2082::AID-CNCR14>3.0.CO;2-D.View ArticlePubMedGoogle Scholar
  12. Slattery ML, Edwards SL, Samowitz W, Potter J: Associations between family history of cancer and genes coding for metabolizing enzymes (United States). Cancer Causes Control. 2000, 11: 799-803. 10.1023/A:1008912317909.View ArticlePubMedGoogle Scholar
  13. Gonzalez FJ, Kimura S: Understanding the role of xenobiotic metabolism in chemical carcinogenesis using gene knockout mice. Mutat Res. 2001, 477: 79-87. 10.1016/S0027-5107(01)00109-9.View ArticlePubMedGoogle Scholar
  14. Chhabra SK, Reed CD, Anderson LM, Shiao YH: Comparison of the polymorphic regions of the cytochrome P450 CYP2E1 gene of humans and patas and cynomolgus monkeys. Carcinogenesis. 2001, 20: 1031-1034.View ArticleGoogle Scholar
  15. Reid JM, Kuffel MJ, Miller JK, Rios R, et al: Metabolic activation of dacarbazine by human cytochromes P450: The role of CYP1A1, CYP1A2, and CYP2E1. Clin Cancer Res. 1999, 5: 2192-2197.PubMedGoogle Scholar
  16. Wang Y, Yang H, Li L, Wang H, et al: Association between CYP2E1 genetic polymorphisms and lung cancer risk: A meta-analysis. Eur J Cancer. 2010, 46: 758-764. 10.1016/j.ejca.2009.12.010.View ArticlePubMedGoogle Scholar
  17. Guengerich FP, Kim DH, Iwasaki M: Role of human cytochrome P450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol. 1991, 4: 168-179. 10.1021/tx00020a008.View ArticlePubMedGoogle Scholar
  18. Kharasch ED, Thummel KE: Identification of cytochrome P450 2E1 as the predominant enzyme catalyzing human liver microsomal defluorination of sevoflurane, isoflurane, and methoxyflurane. Anesthesiology. 1993, 79: 795-807. 10.1097/00000542-199310000-00023.View ArticlePubMedGoogle Scholar
  19. Ulusoy G, Arinç E, Adali O: Genotype and allele frequencies of polymorphic CYP2E1 in the Turkish population. Arch Toxicol. 2007, 81: 711-718. 10.1007/s00204-007-0200-y.View ArticlePubMedGoogle Scholar
  20. Zhou GW, Hu J, Li Q: CYP2E1 Pst/Rsa polymorphism and colorectal cancer risk: A meta-analysis. World J Gastroenterol. 2010, 16: 2949-2953. 10.3748/wjg.v16.i23.2949.PubMed CentralView ArticlePubMedGoogle Scholar
  21. Morita M, Tabata S, Tajima O, Yin G, et al: Genetic polymorphisms of CYP2E1 and risk of colorectal adenomas in the Self Defense Forces Health Study. Cancer Epidemiol Biomarkers Prev. 2008, 17: 1800-1807. 10.1158/1055-9965.EPI-08-0314.View ArticlePubMedGoogle Scholar
  22. Hayashi S, Watanabe J, Kawajiri K: Genetic polymorphisms in the 5'-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene. J Biochem. 1991, 110: 559-565.PubMedGoogle Scholar
  23. Nomura F, Itoga S, Uchimoto T, Tomonaga T, et al: Transcriptional activity of the tandem repeat polymorphism in the 5'-flanking region of the human CYP2E1 gene. Alcohol Clin Exp Res. 2003, 27: 42S-46S. 10.1097/01.ALC.0000078612.01626.96.View ArticlePubMedGoogle Scholar
  24. Gao CM, Takezaki T, Wu JZ, Chen MB, et al: CYP2E1 RsaI polymorphism impacts on risk of colorectal cancer association with smoking and alcohol drinking. World J Gastroenterol. 2007, 13: 5725-5730.PubMed CentralView ArticlePubMedGoogle Scholar
  25. Bouchardy C, Hirvonen A, Coutelle C, Ward PJ, et al: Role of alcohol dehydrogenase 3 and cytochrome P-4502E1 genotypes in susceptibility to cancers of the upper aerodigestive tract. Int J Cancer. 2000, 87: 734-740. 10.1002/1097-0215(20000901)87:5<734::AID-IJC17>3.0.CO;2-E.View ArticlePubMedGoogle Scholar
  26. Tan W, Song N, Wang GQ, Liu Q, et al: Impact of genetic polymorphisms in cytochrome P450 2E1 and glutathione S-transferases M1, T1, and P1 on susceptibility to esophageal cancer among high-risk individuals in China. Cancer Epidemiol Biomarkers Prev. 2000, 9: 551-556.PubMedGoogle Scholar
  27. Yu MW, Gladek-Yarborough A, Chiamprasert S, Santella RM, et al: Cytochrome P450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma. Gastroenterology. 1995, 109: 1266-1273. 10.1016/0016-5085(95)90587-1.View ArticlePubMedGoogle Scholar
  28. Le Marchand L, Sivaraman L, Pierce L, Seifried A, et al: Associations of CYP1A1, GSTM1, and CYP2E1 polymorphisms with lung cancer suggest cell type specificities to tobacco carcinogens. Cancer Res. 1998, 58: 4858-4863.PubMedGoogle Scholar
  29. Hung HC, Chuang J, Chien YC, Chern HD, et al: Genetic polymorphisms of CYP2E1, GSTM1, and GSTT1: Environmental factors and risk of oral cancer. Cancer Epidemiol Biomarkers Prev. 1997, 6: 901-905.PubMedGoogle Scholar
  30. Hildesheim A, Anderson LM, Chen CJ, Cheng YJ, et al: CYP2E1 genetic polymorphisms and risk of nasopharyngeal carcinoma in Taiwan. J Natl Cancer Inst. 1997, 89: 1207-1212. 10.1093/jnci/89.16.1207.View ArticlePubMedGoogle Scholar
  31. Ladero JM, Agundez JA, Rodriguez-Lescure A, Diaz-Rubio M, et al: RsaI polymorphism at the cytochrome P4502E1 locus and risk of hepatocellular carcinoma. Gut. 1996, 39: 330-333. 10.1136/gut.39.2.330.PubMed CentralView ArticlePubMedGoogle Scholar
  32. Kiss I, Sandor J, Pajkos G, Bogner B, et al: Colorectal cancer risk in relation to genetic polymorphism of cytochrome P450 1A1, 2E1, and glutathione-S-transferase M1 enzymes. Anticancer Res. 2000, 20: 519-522.PubMedGoogle Scholar
  33. Yu WP, Chen K, Ma XY, Yao KY, et al: Genetic polymorphism in cytochrome P450 2E1, salted food and colorectal cancer susceptibility: A case-control study. Zhonghua Yufang Yixue Zazhi. 2004, 38: 162-166.PubMedGoogle Scholar
  34. Carriere V, Berthou F, Baird S, Belloc C, et al: Human cytochrome P450 2E1 (CYP2E1): From genotype to phenotype. Pharmacogenetics. 1996, 6: 203-211. 10.1097/00008571-199606000-00002.View ArticlePubMedGoogle Scholar
  35. Itoga S, Nomura F, Makino Y, Tomonaga T, et al: Tandem repeat polymorphism of the CYP2E1 gene: An association study with esophageal cancer and lung cancer. Alcohol Clin Exp Res. 2002, 26: 15S-19S. 10.1111/j.1530-0277.2002.tb02696.x.View ArticlePubMedGoogle Scholar
  36. Le Marchand L, Donlon T, Seifried A, Wilkens LR: Red meat intake, CYP2E1 genetic polymorphisms, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 2002, 11: 1019-1024.PubMedGoogle Scholar
  37. Fritsche E, Pittman GS, Bell DA: Localization, sequence analysis, and ethnic distribution of a 96-bp insertion in the promoter of the human CYP2E1 gene. Mutat Res. 2000, 432: 1-5. 10.1016/S1383-5726(99)00009-6.PubMedGoogle Scholar

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© Henry Stewart Publications 2011