Cytochrome P450 2E1 Polymorphisms Research Articles

NAT2 and CYP2E1 polymorphisms and antituberculosis drug-induced hepatotoxicity in Peruvian patients.

BackgroundIn Peru, 32,970 people were diagnosed with tuberculosis (TB) in 2019. Although TB treatment is effective, 3.4%–13% is associated with significant adverse drug reactions (ADR), considering drug‐induced liver injury (DILI) as the most prevalent. Among the first‐line anti‐TB drugs, isoniazid (INH) is primarily responsible for the occurrence of DILI. INH is metabolized in the liver by the enzymes N‐acetyltransferase‐2 (NAT2) and Cytochrome P450 2E1 (CYP2E1). Based on the previous studies, we hypothesized that the interactions between slow CYP2E1 genotype and NAT2 slow acetylators will induce DILI in TB patients.MethodsIn this cross‐sectional study, all 377 participants completed their anti‐TB treatment, and we genotyped SNPs: rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 for NAT2 and rs3813867 and rs2031920 for CYP2E1.ResultsWe found that rapid, intermediate, and slow NAT2 acetylator were 15%, 38%, and 47%, respectively, in the general population. Intermediate NAT2 acetylator is the least prevalent among patients with adverse reactions (p = 0.024). We did not confirm our hypothesis, however, we found that the combination of intermediate NAT2 acetylators and CYP2E1 c1/c1 genotype significantly protected (OR = 0.16; p = 0.049) against the development of DILI in our population.ConclusionWe propose that the presence of NAT2 intermediate and CYP2E1 c1/c1 genotype could help in therapeutic drug monitoring, and optimize its therapeutic benefits while minimizing its risk for side effects or toxicity.

Genetic polymorphism of the drug-metabolizing enzyme Cytochrome P4502E1 (CYP2E1) in a healthy Saudi population

ObjectivesCytochrome P450 2E1 (CYP2E1) is one of the major enzymes involved in the metabolism and detoxification of various drugs and xenobiotics. Polymorphisms in the CYP2E1 gene exhibit high inter-individual variations associated with alterations in CYP2E1 gene expression and enzyme function. This study aimed to determine the genotype distributions and allele frequencies of CYP2E1*1B, *5B, and *6 polymorphisms among Saudis in western Saudi Arabia. MethodsIn total, 140 healthy Saudis attending King Abdulaziz University Hospital between February and April 2021 were included in the study. CYP2E1 gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. ResultsThe genotype frequencies of CYP2E1*1B A2A2, A2A1, and A1A1 were 54.29%, 40%, and 8%, respectively. The frequencies of CYP2E1*5B c1c1 and c1c2 genotypes were approximately 99.93% and 0.07%, respectively. The frequencies of the CYP2E1*6 DD, DC, and CC genotypes were 91.43%, 7.85%, and 0.72%, respectively. The genotype distributions for these polymorphisms were consistent with the expected distribution based on Hardy-Weinberg equilibrium. The allele frequencies were 74.29% A2 and 25.71% A1 for CYP2E1*1B, 99.64% c1 and 0.36% c2 for CYP2E1*5B, and 95.36% D and 4.65% C for CYP2E1*6. ConclusionThe genotype distribution of CYP2E1*1B polymorphism was higher in the western Saudi population, whereas the CYP2E1*5B and *6 polymorphisms were lower than the global average. Knowledge of the prevalence of CYP2E1 polymorphisms among our population will provide a better understanding of whether individual patients might benefit from their medication or whether they might develop adverse effects.

CYP2E1 Polymorphisms and Colorectal Cancer

Background: The hepatic cytochrome P450 2E1 (CYP2E1) enzyme plays an important role in the metabolic activation of nitrosamines and other carcinogenic compounds. Aim of the study: To determine the effect of chemotherapy and radiation for colorectal cancer patients on some biochemical and molecular parameters. Patients and methods: The current study was conducted in the Department of Biology at the College of Science at the University of Al-Qadisiyah and in cooperation with the Cancer Center in the Najaf city and the Department of Medicine City in Baghdad, Iraq during the period from November 15, 2019, to May 6, 2020. The study group included a total of (90) samples were taken from males and females of ages ranged between (33 years to 80 years) and then it was divided into two groups. The first included (60) samples of people with colorectal cancer (CRC), and the second included (30) samples of people The healthy ones represented the control group. (5ml) of venous blood was withdrawn and the sample was divided into two groups, the first was placed in tubes containing an anti-clotting substance for molecular examination and kept at a temperature (-20) until use, and the other part was placed in Gel tube tubes and then placed in a centrifuge to separate Serum, for the purpose of biochemical examinations. With regard to the results of the values of oxidative stress indicators (SOD, GSH, MDA). Results: there was a significant difference in the level of (SOD, GSH) between the control and treatment groups, where the highest percentage was in the control group, followed by the radiotherapy group and then chemotherapy. The results showed a significant increase in the MDA value of the chemotherapy group compared with the radiotherapy and control group. The results of the molecular study to study the genotypes of the CYPIE2 gene showed that the C1/C1 type is the normal type for the CYPIE2 gene and that the ratio of this type did not show any significant difference between the groups, while the C2/C2 type showed no significant difference between the groups and the C2/C2 type. Conclusion: It can be concluded that the use of radiotherapy and chemotherapy to treat patients with CRC cancer has a clear effect on health and on many of the patient's physiological and biochemical indicators, and this, in turn, is reflected in the patient's ability to fight the disease.

THE ROLE OF CYP2E1 POLYMORPHISM IN THE ACTIVATION OF PROCARCINOGEN METABOLISM OF NASOPHARYNGEAL CARCINOMA

Intoduction:
 Cytochrome P450 2E1 (CYP2E1) is the enzyme as a part of CYP 450 enzyme families. It acts in phase I metabolism which result in the formation of electrophilic molecule and elevation of reactive oxygen species (ROS).
 Review:
 The last is responsible in development of cancer by damaging the protein and DNA, leading to mutation and increase cell proliferation. Nitrosamine as the most carcinogen for nasopharyngeal carcinoma (NPC) is the substrate of this enzyme. This chemical is contained in the salted fish, tobacco smoke, beer, and preserved food such as meat product. Nitrosamine needs CYP2E1 to activate the pro-carcinogen in order to act is carcinogenic effect. Polymorphism of CYP2E1 is associated with higher transcriptional activity and enzyme activity.
 Conclussion:
 It means the ability of this enzyme to activate pro-carcinogen of nitrosamine will increase, leading to higher chance to develop cancer, including NPC.

Association of genetic polymorphisms of CYP2E1, NAT2, GST and SLCO1B1 with the risk of anti-tuberculosis drug-induced liver injury: a systematic review and meta-analysis

ObjectivesThe objective of this study was to investigate the association between genetic polymorphisms of N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1), glutathione S-transferase (GST) and solute carrier organic anion transporter...

Red meat intake, CYP2E1 and PPARγ polymorphisms, and colorectal cancer risk.

The association between red meat intake and colorectal cancer (CRC) may be modulated by genetic polymorphisms of cytochrome P450 2E1 (CYP2E1), a key enzyme in the metabolism of nitrosamines, and peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor involved in adipogenesis and lipid and glucose metabolism. We conducted a case-control study of 971 patients with CRC and 658 controls who were admitted to two university hospitals between 1995 and 2004 in Seoul, Korea. Participants were asked about red meat intake by using a validated food frequency questionnaire. Polymorphisms of CYP2E1 (rs3813867) and PPARγ (rs1801282 or rs3856806) were identified using the TaqMan assay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression models. We found that the association between red meat and CRC varied by CYP2E1 polymorphisms; ORs (95% CIs) for at least five or more vs. less than one time/week of red meat intake were 2.77 (1.23-6.25) among individuals with C alleles of CYP2E1 and 0.89 (0.51-1.54) among individuals with the GG allele (Pinteraction=0.05). Compared with those individuals with the CC allele, increasing risk of CRC with increasing red meat intake was more pronounced among individuals with T alleles of PPARγC161T (rs3856806), but the association was not significant. Our data provide evidence that East Asians with the variant type of CYP2E1 may have high susceptibility to development of CRC risk.

Genetic polymorphism analysis of cytochrome P4502E1 (CYP2E1) in a Chinese Tibetan population.

Cytochrome P4502E1 (CYP2E1) gene genetic polymorphisms vary markedly in frequency among different ethnic and racial groups.We studied the genotype distributions and allele frequencies of 3 CYP2E1 polymorphisms: CYP2E1∗1A, CYP2E1∗7A, and CYP2E1∗7C by polymerase chain reaction technique in a sample of 100 healthy subjects representing Tibetan population.The frequencies of CYP2E1∗1A, ∗7A, and ∗7C alleles were 0.705, 0.125, and 0.170, respectively. Compared with other populations, we found that the allele frequencies of the variants −352A>G (rs2070672) and −333A>T (rs2070673) in this Tibetan population have significant differences compared with European-American, African-American, Japanese, Korean, and other different geographic areas in Chinese Han population. Furthermore, the results of protein prediction revealed that the variant 6397G>A (rs61710826) could influence the protein structure and function.These findings in this study would be valuable for pharmacogenetics for drug therapy and drug discovery. However, further studies in larger samples are warranted to confirm our results.

Genetic Polymorphisms of SLCO1B1, CYP2E1 and UGT1A1 and Susceptibility to Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Chinese Population-Based Prospective Case–Control Study

Drug transporters and drug-metabolizing enzymes have been linked to drug-induced hepatotoxicity. Solute carrier organic anion transporter family member 1B1 (SLCO1B1), cytochrome P450 2E1 (CYP2E1), and UDP glucuronosyltransferase 1A1 (UGT1A1) were selected as candidate genes to explore their association with susceptibility to anti-tuberculosis drug-induced hepatotoxicity (ATDH). Thirty-four tag single nucleotide polymorphisms (tagSNPs) in SLCO1B1, CYP2E1, and UGT1A1 with 10-kb expansion up- and down-stream were genotyped in 461 patients with ATDH and 466 patients without ATDH in a prospective 1:1 matched case-control study. The frequencies and distributions of genotypes and haplotypes were compared between the groups using three genetic models (dominant, recessive, and additive) to identify associations with susceptibility to ATDH. Patients with the rs4149034 G/A, rs1564370 G/C, and rs2900478 T/A genotypes of SLCO1B1 had a significantly lower risk of ATDH, while those carrying the rs2417957 T/T and rs4149063 T/T genotypes had an increased risk. The rs4148323 A/A genotype of UGT1A1 was found to significantly reduce the risk of ATDH. Haplotype analysis showed the TGTG, TTTC, and GTTC haplotypes of SLCO1B1 were associated with an increased ATDH risk, whereas the GACC haplotype was related to a reduced risk. The ATG haplotype of UGT1A1 reduced the risk of ATDH. Moreover, treatment outcomes in tuberculosis patients were further affected by genetic variants of SLCO1B1. Genetic polymorphisms of SLCO1B1 and UGT1A1 were found to be associated with susceptibility to ATDH. Molecular identification of susceptibility genes provides a theoretical foundation for predicting the likelihood of ATDH and predicting treatment outcomes in tuberculosis patients.

Polymorphisms of Cytochrome P450 2E1 Gene and Gastric Cancer Risk: A Case Control Study from West Bengal, India

Background: RsaI/PstI and DraI polymorphisms of cytochrome P450 2E1 (CYP2E1) gene are regarded as the most common polymorphisms associated with gastric cancer (GC). Very few data of these polymorphisms have been reported from India with regard to GC risk. We evaluated RsaI: -C1053T (rs2031920), PstI: -G1295C (rs3813867) site in the 5’ flanking region, DraI: T7668A (rs6413432) site in intron 6, -G71T rs6413420 and G4768A or V179I rs6413419 polymorphisms of CYP2E1 with GC risk in the population of West Bengal, India. Methods: We enrolled 105 GC patients (cases) and corresponding sex, age and ethnicity matched normal 108 individuals (controls) for the study. Genotyping for rs6413419, rs6413420, rs6413432, rs2031920, rs3813867 of CYP2E1 was performed using DNA sequencing and RFLP analysis. Results and conclusion: Our results suggest that the difference between genotype frequencies of rs3813867 and rs2031920, although not statistically significant but the allele frequencies of rs3813867 (OR=2.29, 95% CI=1.01-5.18, p=0.042) and rs2031920 (OR=2.29, 95% CI=1.01-5.18, p=0.042) showed significant difference between GC and control individuals. This when pooled with smoking augmented GC risk by nearly 4-fold. Therefore, a larger population is needed to be screened to confirm the association of these studied SNPs with GC in India.

Association between effectiveness of tuberculosis treatment and cytochrome P-4502E1 polymorphism of the patients.

The risk of antituberculosis (TB) drug-induced liver injury could be determined by patients' genotype polymorphism of the xenobiotic-metabolizing enzymes. To find the meaning of cytochrome P-4502E1 (CYP2E1) polymorphism in TB patients. Corresponding of CYP2E1 polymorphism in TB patients with the level of isoniazid and rifampicin as well as for the outcome and toxicity development during inpatient TB treatment. CYP2E1 genotype was detected with the help of polymerase chain reaction and endonuclease analysis. The level of rifampicin, isoniazid, diene conjugates (DC), and catalase activity in the blood was determined spectrophotometrically. We have considered medical records at the beginning and at the end of inpatient treatment. Kruskal-Wallis, ANOVA, and Chi-square tests were used in this study. The concentration of rifampicin 6 h after its intake was 17.6% higher in carriers of slow metabolizer (SM) CYP2E1 genotype than in patients with rapid metabolizer (RM) genotype that proved a participation of hepatic enzyme CYP2E1 in metabolism of rifampicin. According to obtained results in TB patients with RM genotype, the indexes of cytolysis (alanine aminotransferase, aspartate aminotransferase) and bile stasis (gamma-glutathione transferase) were higher comparatively to SM genotype both before and after inpatient treatment. This correlated with a higher concentration of DC in the blood (+8.6%) and lower plasma catalase activity (-50.0%) in the patients with RM genotype comparatively with the patients with SM genotypes. Polymorphism of CYP2E1 genotype is an important criterion for the development of hepatotoxicity before and during TB treatment while increased rifampicin level has no influence on it.

CYP2E1 polymorphisms and nasopharyngeal carcinoma risk: a meta-analysis.

The cytochrome P450 2E1 (CYP2E1) polymorphisms have been implicated in susceptibility to nasopharyngeal carcinoma (NPC). However, the results are inconsistent. The aim of this meta-analysis is to evaluate the association between the CYP2E1 polymorphisms and NPC risk. All eligible case-control studies published up to April 4, 2016 were identified by searching PubMed, Web of Science, CNKI, Wanfang and Weipu databases. The NPC risk associated with the CYP2E1 polymorphism was estimated for each study by odds ratios (OR) together with its 95% confidence interval (CI), respectively. Seven case-control studies were included. Of those, there were seven studies (1302 cases and 1319 controls) for RsaI/PstI polymorphism and three studies (732 cases and 642 controls) for DraI polymorphism. Overall, a significant association was found for RsaI/PstI polymorphism under recessive and homozygote comparison models (OR=2.72, 95% CI 1.73-4.25; OR=2.64, 95% CI 1.68-4.16, respectively), while there was no significant association for RsaI/PstI polymorphism under other two genetic models. When stratified by ethnicity, similar results were observed between them. As for DraI polymorphism, we also observed a significant association under recessive and homozygote comparison models, but not for the other two models. This meta-analysis suggests that the CYP2E1 polymorphisms contributed to the susceptibility of NPC, especially in Asian populations.

Association between CYP2E1 polymorphisms and risk of gastric cancer: An updated meta-analysis of 32 case-control studies.

Previous studies suggested that RsaI/PstI and DraI polymorphisms on cytochrome P450 2E1 (CYP2E1) may be associated with susceptibility to gastric cancer (GC). However, this association remains ambiguous. A meta-analysis of previously published studies was performed in an attempt to elucidate this association. The odds ratio and 95% confidence interval were used to assess the strength of the association. In the overall analyses of RsaI/PstI and DraI, no association was identified. In the subgroup analyses, RsaI/PstI was identified to increase the risk of GC in the smoking population. In addition, in the previous studies of interactions with other genes, RsaI/PstI was revealed to be associated with increased GC risks when glutathione S-transferase-µ-1 or glutathione S-transferase θ-1 was null or DraI was homozygous wild-type. However, these stratified analyses were lacking credibility due to the limitation of correlational study numbers. In conclusion, CYP2E1 polymorphisms revealed no association with the risk of GC.

Association between CYP2E1 polymorphisms and risk of differentiated thyroid carcinoma.

Differentiated thyroid carcinoma (DTC) results from complex interactions between genetic and environmental factors. Known etiological factors include exposure to ionizing radiations, previous thyroid diseases, and hormone factors. It has been speculated that dietary acrylamide (AA) formed in diverse foods following the Maillard's reaction could be a contributing factor for DTC in humans. Upon absorption, AA is biotransformed mainly by cytochrome P450 2E1 (CYP2E1) to glycidamide (GA). Considering that polymorphisms within CYP2E1 were found associated with endogenous levels of AA-Valine and GA-Valine hemoglobin adducts in humans, we raised the hypothesis that specific CYP2E1 genotypes could be associated with the risk of DTC. Analysis of four haplotype tagging SNPs (ht-SNPs) within the locus in a discovery case-control study (N=350/350) indicated an association between rs2480258 and DTC risk. This ht-SNP resides within a linkage disequilibrium block spanning intron VIII and the 3'-untranslated region. Extended analysis in a large replication set (2429 controls and 767 cases) confirmed the association, with odds ratios for GA and AA genotypes of 1.24 (95% confidence interval (CI) 1.03-1.48) and 1.56 (95% CI, 1.06-2.30), respectively. Functionally, the minor allele was associated with low levels of CYP2E1 mRNA and protein expression as well as lower enzymatic activity in a series of 149 human liver samples. Our data support the hypothesis that inter-individual differences in CYP2E1 activity could modulate the risk of developing DTC suggesting that the exposure to specific xenobiotics, such as AA, could play a role in this process.

Analysis of ADH1B Arg47His, ALDH2 Glu487Lys, and CYP4502E1 polymorphisms in gastric cancer risk and interaction with environmental factors.

Gastric cancer is the fourth commonly diagnosed cancer and the second most frequent cause of cancer death worldwide. Genetic variations in ADH1B and ALDH2 may alter the function and activity of the corresponding enzymes, leading to differences in acetaldehyde exposure between drinkers. Cytochrome P4502E1 (CYP4502E1) is a phase I enzyme that plays an important role in metabolizing nitrosamine compounds and the bioactivation of procarcinogens. During the period of July 2013 to July 2015, 246 patients and 274 controls were enrolled from the First Affiliated Hospital of Jinan University. In the codominant model, the AA genotype of ALDH2 Glu487Lys significantly elevated the risk of gastric cancer in comparison with the GG genotype of ALDH2 Glu487Lys. In the recessive model, the AA genotype of ALDH2 Glu487Lys significantly increased the risk of gastric cancer compared to the GG+GA genotype (OR = 2.34 95%CI = 1.02-5.70). We found in the codominant model that individuals harboring the C2/C2 genotype of CYP4502E1 had a higher risk of developing gastric cancer than those with the C1/C1 genotype. In addition, in the recessive model, we found that the C2/C2 genotype correlated with an elevated risk of gastric cancer in comparison with the C1/C1+C1/C2 genotype (OR = 4.90, 95%CI = 2.04-13.51). However, no significant relationship was measured between ADH1B Arg47His and gastric cancer risk. In summary, the results of our study indicate that ALDH2 Glu487Lys and CYP4502E1 polymorphisms could be risk factors for the development of gastric cancer in the Chinese population.

Evaluation of cytochrome P4502E1 polymorphisms in healthy adult Western Indians and patients with antituberculous drug-induced hepatotoxicity.

Objectives:Cytochrome P4502E1 (CYP2E1) is involved in the metabolism of isoniazid and the mediation of its hepatotoxicity. It exhibits genetic polymorphism in humans. This study evaluated the polymorphism of CYP2E1 in adult healthy Western Indians and patients on antituberculous drugs by phenotyping and genotyping.Methods:A 500 mg single dose of chlorzoxazone (CZX) was administered to 136 healthy adult Western Indian participants. Venous blood samples 2 h postdose were analyzed for the levels of CZX and 6-hydroxy CZX, and the metabolic ratio (MR) was calculated to determine the extent of rapid and poor metabolizers using probit plot analysis. Patients on antituberculous drugs who had raised the liver enzymes or clinical symptoms of hepatotoxicity were also recruited. Genotyping for CYP2E1 * 5B allele was performed by polymerase chain reaction – rapid fragment length polymorphism technique.Results:A total of 139 healthy participants were enrolled, of which the final analysis consisted of data from 136 participants for genotyping and 137 for phenotyping. Only 1 participant had reported mild drowsiness 2 h postdose, and no other adverse events were observed. The median (range) MR of population was 0.2 (0.1–4.0), and no polymorphisms were detected using phenotype data. A total of 134/136 (98.5%) had c1/c1 genotype and 1/136 each (0.75%) had c1/c2 and c2/c2 genotypes, respectively. Of the 2/136 participants harboring c2 allele, one had MR of 0.1 (c1/c2) and another had 0.5 (c2/c2). A total of 25 cases of antituberculous drug-induced hepatotoxicity and 50 control patients were recruited, of which finally 22 cases and 49 controls were available for evaluation. All the cases had c1/c1 genotype while 42/49 (85.7%) controls had c1/c1, 6/49 (12.2%) had c1/c2, and 1/49 (2.1%) had c2/c2 genotype and the crude odds ratio was 7.9 (0.4, 145.6).Conclusions:A background prevalence of CYP2E1*B polymorphism and their activity in Western Indian population was observed. The study suggests no association between the CYP2E1 genotyping with antituberculous drug-induced hepatotoxicity.

Single-Nucleotide Polymorphisms in Cytochrome P450 2E1 (CYP2E1) 3'-Untranslated Region Affect the Regulation of CYP2E1 by miR-570.

Human cytochrome P450 2E1 (CYP2E1) catalyzes the metabolism of numerous xenobiotics, including acetaminophen and ethanol. CYP2E1 expression is known to be extensively regulated by post-transcriptional and post-translational mechanisms. A previous study had reported that a single-nucleotide polymorphism (SNP) 1561A>G in the 3'-untranslated region (3'-UTR) of CYP2E1 leads to a decreased CYP2E1 mRNA level in human peripheral blood mononuclear cells. In this study, we examined the possibility that microRNA(s) (miR) may be involved in the SNP-mediated modulation of CYP2E1 expression. Genotyping and sequencing analyses revealed that another SNP, 1556T>A, in the 3'-UTR was in complete linkage disequilibrium with the SNP 1561A>G. We termed the alleles with 1556T and 1561A or 1556A and 1561G haplotype I or II, respectively. A luciferase assay revealed that miR-570 recognizes the CYP2E1 3'-UTR of haplotype I but not haplotype II. Human embryonic kidney 293 (HEK293) cell lines stably expressing human CYP2E1 that included the 3'-UTR of haplotype I or II (HEK/2E1(I) or HEK/2E1(II) cells, respectively) were established. Overexpression of miR-570 significantly decreased the CYP2E1 protein level in the HEK/2E1(I) cells but not in the HEK/2E1(II) cells. In seven human livers with diplotype I/I, the CYP2E1 protein levels were inversely correlated with the miR-570 levels, but no relationship was observed in 25 human livers with diplotypes I/II and II/II. Collectively, it was demonstrated that human CYP2E1 was regulated by miR-570 in a genotype-dependent manner. This report describes the first proof that SNP in 3'-UTR of human P450 affects binding of miRNA to modulate the expression in the liver.

CYP2E1 PstI polymorphism increases cervical neoplasia risk: a meta-analysis.

Cytochrome P4502E1 (CYP2E1) is a key enzyme in the metabolic activation of many carcinogens, but the roles of CYP2E1 polymorphisms in cervical neoplasia (CN) are inconclusive. Published case-control cohort studies from the Pubmed, Embase, and China National Knowledge Infrastructure databases were retrieved. Data were extracted and pooled odds ratios with 95% confidence intervals were calculated. Seven studies examining 1097 cases and 1117 controls were included in this meta-analysis. The pooled effect size showed no association between CYP2E1 RsaI and DraI polymorphisms and CN risk in a codominant model. However, using a recessive model, an association between the PstI polymorphism and CN risk was observed (odds ratio: 2.10, 95% confidence interval: 0.96-4.62, P = 0.06), indicating that individuals with the homozygous rare genotype have a higher risk of developing CN compared to those with homozygous wild-type and heterozygous genotypes. When stratified by ethnicity, the PstI polymorphism was significantly correlated with CN susceptibility in non-Asians (odds ratio: 3.74, 95% confidence interval: 1.13-12.43, P = 0.03). This meta-analysis suggests that the CYP2E1 PstI polymorphism increases the risk of CN in non-Asians.

Abstract 3252: A regulatory variant in CYP2E1 affects the risk of lung squamous cell carcinoma

Abstract Background: Cytochrome P450 2E1 (CYP2E1), an ethanol-inducible enzyme, has been shown to metabolically activate various carcinogens, which is critical for the development of cancers. It has demonstrated that CYP2E1 polymorphisms alter the transcriptional activity of the gene. However, studies on the association between CYP2E1 PstI polymorphism and non-small cell lung cancer have reported conflicting results. Thus, the gain of the present study was to investigate whether CYP2E1 PstI polymorphism is associated with the development of non-small cell lung cancer in Chinese population. Method: A case-control study was conducted in which CYP2E1 PstI polymorphism was analyzed in 526 Chinese patients with non-small cell lung cancer and 526 age-matched healthy controls by PCR-RFLP. Odds ratios were estimated by multivariate logistic regression. Result: For CYP2E1 PstI polymorphism, C allele carriers (OR=0.67; CI=0.51-0.87; P=0.002) was associated with a decreased risk of non-small cell lung cancer when compared with GG homozygotes. In the group analyses by pathological types, for lung SCC and other types the ORs of the C allele carriers were (OR=0.60; CI=0.41-0.88; P=0.009) and (OR=0.54; CI=0.30-0.99; P=0.045), respectively. In the group analyses by smoking status, there was a significant association among nonsmokers (OR=0.57; CI=0.40-0.81; P=0.002), but not smokers. In the group analyses by TNM stage, there was no significance between CYP2E1 PstI polymorphism and the grade of non-small cell lung cancer. Conclusion: CYP2E1 PstI polymorphism is associated with decreased risk of development of non-small cell lung cancer and lung SCC or other types in Chinese patients. Key Words: lung cancer; CYP2E1; gene polymorphism; susceptibility; genetic variant Citation Format: Lei Cao, Jia Lin, Bing He, Hongge Wang, Juan Rao, Yingwen Liu, Xuemei Zhang. A regulatory variant in CYP2E1 affects the risk of lung squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3252. doi:10.1158/1538-7445.AM2014-3252

Cytochrome P450 2E1 gene polymorphism and alcohol drinking on the risk of hepatocellular carcinoma: a meta-analysis.

The gene polymorphism of Cytochrome P450 2E1 (CYP2E1) is supposed to be associated with cancer susceptibility. Many studies focusing on the Pst I/Rsa I polymorphism of CYP2E1 gene and hepatocellular carcinoma (HCC) risk have been conducted and the results are conflicting. In the current study, a meta-analysis of published studies was performed to assess the association between CYP2E1 Pst I/Rsa I polymorphism and risk to HCC. 11 studies containing 1,178 cases and 1,623 controls were selected to determine whether c2 allele of CYP2E1 gene can increase HCC susceptibility, especially through interacting with alcohol drinking. Using the random effects model, the result indicated that there was no association between CYP2E1 Pst I/Rsa I genotype and HCC risk [odds ratio (OR) 1.03 (95% confidence interval (CI): 0.76-1.40) for c2 variant allele and OR 0.82 (95% CI: 0.51-1.31) for c2 homozygotes compared with wild-type homozygotes]. The association between CYP2E1 (c2) variant allele and HCC susceptibility were found when interacting with alcohol [OR 2.88 (95% CI: 1.25-6.60)]. In conclusion, this meta-analysis results showed that Pst I/Rsa I polymorphism of CYP2E1may slightly increase the risk of HCC and alcohol consumption increases the probability of developing HCC, especially for the carriers of some CYP2E1 alleles. CYP2E1 Pst I/Rsa I polymorphism may contribute to the proportion cases of HCC, which needs further investigations.

Polymorphisms in CYP2E1, GSTM1 and GSTT1 and anti-tuberculosis drug-induced hepatotoxicity

Anti-tuberculosis drug-induced hepatitis (ATD- induced hepatitis) has been linked to polymorphisms in genes encoding drug metabolizing enzymes. N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferase (loci GSTM1 and GSTT1) are involved in the metabolism of isoniazid, the most toxic drug for the treatment of tuberculosis (TB). This study was designed to determine the frequency and to evaluate whether polymorphisms at CYP2E1, GSTM1 and GSTT1 genes are associated with drug response, as well as to identify clinical risk factors for ATD-induced hepatitis. A total of 245 Brazilian patients undergoing treatment for TB were genotyped using polymerase chain reaction and restriction fragment length polymorphism and sequencing methods. The frequencies of the CYP2E1 polymorphic alleles RsaI, PstI and DraI are 8%, 8.5% and 12%, respectively. GSTM1 and GSTT1 genes are deleted in 42.9% and 12.4% of the population, respectively. Fifteen patients (6.1%) developed hepatotoxicity. Clinical (HIV, female sex and extrapulmonary TB) and genetic characteristics (CYP2E1 without any mutations, having NAT2 slow acetylator profile) are at higher risk of developing ATD-induced hepatitis in this population. Genotyping for GSTM1 and GSTT1 showed no influence on drug response.