A comparison of Val81Met and other polymorphisms of alcohol metabolising genes in patients and controls in Northern Spain

The aim of this paper is to study polymorphism in the TH, ADH1B, ADH1C, ALDH2 and CYP2E1 genes so as to ascertain whether it is associated with excessive consumption of alcohol. The SNPs rs6356 of TH, rs1229984, rs2066702 of ADH1B; rs698, rs1693482 of ADH1C; rs671 of ALDH2; rs72559710, rs55897648, rs6413419, rs3813867, rs2031920, rs6413432 of CYP2E1 were studied in a sample of 172 high-level patients and 150 fully non-drinkers controls. Genotyping was performed using Rt-PCR with Taqman probes. SNPs located at ALDH2 and CYP2E1 showed no heterozygosity. Frequency distribution showed significant differences between the two groups studied for loci TH and ADH1B. The genotype Val/Val of TH locus increased in risk 1.988 times (95% CI: 1.006–3.930) that the subjects carrying the genotype Met/Met; and the genotype ADH1B*1/*1 of ADH1B locus increased in risk 3.811 times (CI: 1.660–8.749) that the subjects carrying the genotype ADH1B*1/*2. Alleles Val and ADH1B*1 may therefore increase the risk of the onset and development of this illness.     

Effect of polymorphic metabolizing genes on micronucleus frequencies among benzene-exposed shoe workers in China

It is well-known that metabolism of benzene is required for the induction of toxicity and consequent health problems. Therefore, genetic variation in benzene (BZ) metabolism genes can influence health outcomes. However, large population studies are needed to provide more evidence for such relationship. We have conducted a large population investigation (385 BZ-exposed shoe workers and 197 matched healthy controls) on the association between inheritance of certain BZ metabolizing genes and the expression of micronuclei (MN). The latter was based on the cytokinesis-blocked MN assay. We analyzed the polymorphisms of GSTM1, GSTT1, GSTP1 (rs1695), CYP2E1 (rs3813867), CYP2E1 (rs2031920), CYP2E1 (rs6413432), mEH exon 3 (rs1051740), mEH exon 4 (rs2234922). Univariate Poisson regression analysis demonstrated that the BZ-exposed workers had significantly increased MN frequency compared with the controls (FR = 1.84, 95% CI: 1.56–2.18; P < 0.001), and showed a cumulative exposure dose–response relationship. The CYP2E1 rs3813867 mutant allele (CC + GC) (FR 1.15, 95% CI 1.02–1.29; P = 0.020) and rs2031920 variant allele (CT + TT) (FR = 1.23, 95% CI: 1.09–1.37, P < 0.01) was associated with higher MN frequency significantly compared with the wild genotype separately. Furthermore, the MN frequency in rs2031920 variant allele (CT + TT) (FR = 1.17, 95% CI: 1.04–1.31, P < 0.01) was also higher than the wild genotype when the age, gender and cumulative exposure dose was adjusted in Poisson regression. In addition, the CYP2E1, however, GSTM1null, GSTT1null, GSTP1 rs1695, rs6413432, rs1051740 and rs2234922 polymorphisms showed no association with MN frequency. Our results indicate that two promoter polymorphisms in the CYP2E1 gene, especially the rs2031920 variant allele, were involved with the BZ-induction of MN and may contribute to risk of cancer among exposed workers.     

Genetic polymorphisms of<Emphasis Type="Italic">CYP2A6</Emphasis> and<Emphasis Type="Italic">CYP2E1</Emphasis> with tobacco smoking is not associated with risk of urothelial cancer

Objectives  To elucidate the association between genetic polymorphisms ofCYP2a6 andCYP2E1 and urothelial cancer susceptibility. Methods  A total of 137 Japanese patients with urothelial cancer and 217 Japanese healthy controls, frequency-matched for age and gender, were selected. The polymorphisms ofCYP2A6 andCYP2E1 were analyzed by PCR-RFLP, and cigarette smoking histories were obtained through interviews Results  The frequency ofCYP2A6 homozygote deletion genotype was 2.9% in the patients, compared with 3.2% in the controls (OR=0.84, 95% CI 0.24–2.96). The frequencies ofCYP2E1 C1/c2 andC2/c2 were 27.7% and 4.4% in the patients, compared with 35.5% and 6.0% in the controls (OR=0.68, 95% CI 0.42–1.09, OR=0.67, 95% CI 0.24–1.84, respectively). No statistically significant differences were observed when theCYP2A6 homozygote deletion genotype and theCYP2E1 genotypes were examined relative to smoking status. Conclusions  Our data indicate that neither a relationship between genetically impaired nitrosamine metabolism and tobacco-smoking consumption, nor urothelial cancer risk related to theCYP2A6 deletion genotype andCYP2E1 Rsa I genotype was found in Japanese population.     

ALDH2和CYP2E1基因多态性及饮酒习惯与肝细胞癌易感性的关系

目的研究乙醛脱氢酶2(ALDH2)和细胞色素P4502E1(CYP2E1)基因多态性与饮酒因素交互作用在广西原发性肝细胞癌发生中的作用。方法对广西壮族自治区300例肝细胞癌和292例正常对照进行流行病学调查研究,并用PCR-RFLP方法检测ALDH2和CYP2E1基因型。结果病例和对照组中ALDH2和CYP2E1变异基因型携带者分别占50.3%、48.0%和32.3%、32.9%(P0.05)。饮酒频度每周≥3次(高频饮酒)且携带变异基因ALDH2和CYP2E1者发生肝癌的危险度分别是饮酒频度每周3次(低频饮酒)且携带野生基因型者的3.334倍(95%CI=1.746～6.406)和1.803倍(95%CI=0.974～3.336),同时携带两变异基因型者患肝癌风险为1.200倍(95%CI=0.730～1.972),且饮酒增加两变异基因型携带者的肝癌发病风险(OR=1.816,95%CI=0.985～3.348)。结论单一ALDH2或CYP2E1基因型与肝细胞癌易感性无关;但高频饮酒且携带变异基因ALDH2或CYP2E1者患肝癌风险增加,且两变异基因型单倍体增加肝癌发病风险。提示乙醇在增加肝癌发病风险的过程中存在基因-环境和基因-基因相互作用。     

The association between CYP2E1 polymorphisms and hepatotoxicity due to anti-tuberculosis drugs: A meta-analysis

BackgroundAlthough there have been previous studies on the potential association between cytochrome P450 2E1 (CYP2E1) polymorphisms and the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH), the results have generally been controversial.MethodsWe searched Medline/PubMed, EMBASE, Web of Science, and the Cochrane Library using the following key words: cytochrome P450 2E1, CYP2E1, polymorphism, tuberculosis and TB. The strength of the association between the CYP2E1 PstI/RsaI and DraI polymorphism and ATDH risk as measured by odds ratios (OR) with 95% confidence intervals (CIs) was studied.ResultsCompared with the wild genotype (c1/c1), the OR of ATDH was 1.41 (95% CI: 1.1–1.82, P = 0.007) for the PstI/RsaI polymorphism, and 0.78 (95% CI: 0.51–1.18, P = 0.23) for the DraI polymorphism. Compared with individuals with N-acetyltransferase 2 (NAT2) fast or intermediate acetylator genotype and c1/c1 genotype patients who were NAT2 slow acetylators and carried the high activity CYP2E1 c1/c1 genotype had higher risk for ATDH (OR = 3.10, P < 0.0001).ConclusionThe present meta-analysis indicates that the CYP2E1 c1/c1 genotype may be a risk factor for ATDH, and the concomitant presence of the slow acetylator NAT2 genotype may further increase this risk.     

Alcohol consumption, alcohol dehydrogenase 1C (ADH1C) genotype, and risk of colorectal cancer in the Netherlands Cohort Study on diet and cancer

Within the Netherlands Cohort Study (1986), we examined associations between alcohol consumption, the alcohol dehydrogenase 1C (ADH1C) genotype, and risk of colorectal cancer (CRC). After a follow-up period of 7.3 years, 594 CRC cases with information on genotype and baseline alcohol intake were available for analyses. Adjusted incidence rate ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In subjects who reported to have consumed equal amounts of total alcohol both 5 years before baseline and at baseline, drinkers of ≥30 g of alcohol per day with the ADH1C*2/*2 genotype were associated—although not statistically significant—with an increased risk of CRC relative to abstainers with the ADH1C*1/*1 genotype (RR: 1.91, 95% CI: 0.68, 5.34). The risk estimate in this exposure group increased slightly when compared with light drinkers of ≥0.5-<5 g/day with the ADH1C*1/*1 genotype (RR: 2.32, 95% CI: 0.80, 6.72). The interaction term however, was not statistically significant (P > .05). In subjects who reported to have consumed equal amounts of total alcohol both 5 years before baseline and at baseline, drinkers of ≥30 g of alcohol per day were associated—although not statistically significant—with an increased risk of CRC relative to abstainers (RR: 1.38, 95% CI: 0.80, 2.38). This risk estimate for high-level drinkers became stronger when compared with light drinkers (RR: 1.74, 95% CI: 1.01, 2.99). As main effect of genotype, we observed that the ADH1C*2/*2 genotype was associated with a 42% increase in risk of CRC when compared with the ADH1C*1/*1 genotype. In conclusion, both genotype and alcohol consumption were associated with an increased risk of CRC. Owing to limited statistical power, we found no apparent evidence for the ADH1C genotype as effect modifier of the relationship between alcohol intake and CRC. Nevertheless, the interaction deserves further investigation in larger genetic epidemiologic studies.     

Relationships of alcohol dehydrogenase 1B (<Emphasis Type="Italic">ADH1B</Emphasis>) and aldehyde dehydrogenase 2 (<Emphasis Type="Italic">ALDH2</Emphasis>) genotypes with alcohol sensitivity,drinking behavior and problem drinking in Japanese older men

Objectives

Many East Asians have the genetic polymorphisms rs1229984 in alcohol dehydrogenase 1B (ADH1B) and rs671 in aldehyde dehydrogenase 2 (ALDH2). Here we analyzed the relationships of the two genotypes with alcohol sensitivity, drinking behavior and problem drinking among older and younger men living in rural areas of Japan.

Methods

The subjects were 718 Japanese men aged 63.3 ± 10.8 (mean ± SD), categorized into the older (≥65 years, n = 357) and younger (<65 years, n = 361) groups. Facial flushing frequency, drinking behavior and positive CAGE results were compared among the genotypes using Bonferroni-corrected χ² test and a multivariate logistic regression analysis adjusting for age, BMI and lifestyle factors.

Results

The frequency of ‘always’ facial flushing among the ADH1B*1/*2 carriers was significantly lower than that among the ADH1B*2/*2 carriers in the older group (P < 0.01). The alcohol consumption (unit/day) in the ADH1B*1/*2 carriers tended to be higher compared with that in the ADH1B*2/*2 carriers among the older group (P = 0.050). In the younger group, no significant differences in alcohol sensitivity and drinking habits were generally found among the ADH1B genotypes. The ADH1B*1/*1 genotype tended to be positively associated with problem drinking in the older group (P = 0.080) but not in the younger group. The ALDH2 genotypes consistently and strongly affected the alcohol sensitivity, drinking behavior and problem drinking in both the younger and older group.

Conclusions

We for the first time observed a significant difference in alcohol sensitivity between ADH1B*1/*2 and ADH1B*2/*2 in older men aged 65 and above.

     

Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human large bowel: association of the functional polymorphisms of ADH and ALDH genes with hemorrhoids and colorectal cancer

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol. Functional polymorphisms of ADH1B, ADH1C, and ALDH2 genes occur among racial populations. The goal of this study was to systematically determine the functional expressions and cellular localization of ADHs and ALDHs in human rectal mucosa, the lesions of adenocarcinoma and hemorrhoid, and the genetic association of allelic variations of ADH and ALDH with large bowel disorders. Twenty-one surgical specimens of rectal adenocarcinoma and the adjacent normal mucosa, including 16 paired tissues of rectal tumor, normal mucosae of rectum and sigmoid colon from the same individuals, and 18 surgical mixed hemorrhoid specimens and leukocyte DNA samples from 103 colorectal cancer patients, 67 hemorrhoid patients, and 545 control subjects recruited in previous study, were investigated. The isozyme/allozyme expression patterns of ADH and ALDH were identified by isoelectric focusing and the activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting using the corresponding purified class-specific antibodies; the cellular activity and protein localizations were detected by immunohistochemistry and histochemistry, respectively. Genotypes of ADH1B, ADH1C, and ALDH2 were determined by polymerase chain reaction-restriction fragment length polymorphisms. At 33 mM ethanol, pH 7.5, the activity of ADH1C*1/1 phenotypes exhibited 87% higher than that of the ADH1C*1/*2 phenotypes in normal rectal mucosa. The activity of ALDH2-active phenotypes of rectal mucosa was 33% greater than ALDH2-inactive phenotypes at 200 μM acetaldehyde. The protein contents in normal rectal mucosa were in the following order: ADH1 > ALDH2 > ADH3 ≈ ALDH1A1, whereas those of ADH2, ADH4, and ALDH3A1 were fairly low. Both activity and content of ADH1 were significantly decreased in rectal tumors, whereas the ALDH activity remained unchanged. The ADH activity was also significantly reduced in hemorrhoids. ADH4 and ALDH3A1 were uniquely expressed in the squamous epithelium of anus at anorectal junctions. The allele frequencies of ADH1C*1 and ALDH2*2 were significantly higher in colorectal cancer and that of ALDH2*2 also significantly greater in hemorrhoids. In conclusion, ADH and ALDH isozymes are differentially expressed in mucosal cells of rectum and anus. The results suggest that acetaldehyde, an immediate metabolite of ethanol, may play an etiological role in pathogenesis of large bowel diseases.     

Alcohol drinking, mean corpuscular volume of erythrocytes, and alcohol metabolic genotypes in drunk drivers

Regular and irregular abuse of alcohol are global health priorities associated with diseases at multiple sites, including cancer. Mechanisms of diseases induced by alcohol are closely related to its metabolism. Among conventional markers of alcohol abuse, the mean corpuscular volume (MCV) of erythrocytes is prognostic of alcohol-related cancer and its predictivity increases when combined with functional polymorphisms of alcohol dehydrogenase (ADH1B [rs1229984] and ADH1C [rs698]) and the mitochondrial aldehyde dehydrogenase (ALDH2 [rs671]). Whether these genetic variants can influence abuse in alcohol drinking and MCV has never been examined in drunk-driving traffic offenders. We examined 149 drunk drivers, diagnosed as alcohol abusers according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition Text Revision (DSM-IV-TR) and enrolled in a probation program, and 257 social drinkers (controls), all Caucasian males. Alcohol intake was assessed according to self-reported drink-units/d and MCV unadjusted and adjusted for age, smoking, and body mass index. Multivariable models were used to compute MCV adjusted means. Genotype analyses were performed by PCR on DNA from blood. The adjusted MCV mean was higher in drunk-driving abusers than in controls (92 vs. 91 fL; P < .0001) and increased with the number of drink-units/d in both abusers and controls (P-trend = .0316 and .0089) already at intermediate quantities (0-1 vs. 2-4 drink-units/d: P = .054 and .024). Carriers of the common ADH1B*1/*1 (rs1229984) genotype were more likely to be drunk-driving abusers (P = .008), reported higher drink-units/d (P = .0126), and had larger MCV (P = .035). The rs698 ADH1C and rs671 ALDH2 polymorphisms were not associated with MCV. ADH1B*1/*1 polymorphism is significantly associated with being a drunk-driving abuser, higher alcohol drinking, and MCV enlargement. This suggests that drunk drivers with augmented MCV modulated by the alcohol metabolic ADH1B*1/*1 genotype may be at higher risk of driving incapability and of alcohol-related cancer.     

Polymorphisms in GSTT1, GSTZ1, and CYP2E1, Disinfection By-products,and Risk of Bladder Cancer in Spain

Background

Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water.

Objectives

In this study we investigated the combined influence of DBP exposure and polymorphisms in glutathione S-transferase (GSTT1, GSTZ1) and cytochrome P450 (CYP2E1) genes in the metabolic pathways of selected by-products on bladder cancer in a hospital-based case–control study in Spain.

Methods

Average exposures to trihalomethanes (THMs; a surrogate for DBPs) from 15 years of age were estimated for each subject based on residential history and information on municipal water sources among 680 cases and 714 controls. We estimated effects of THMs and GSTT1, GSTZ1, and CYP2E1 polymorphisms on bladder cancer using adjusted logistic regression models with and without interaction terms.

Results

THM exposure was positively associated with bladder cancer: adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.2 (0.8–1.8), 1.8 (1.1–2.9), and 1.8 (0.9–3.5) for THM quartiles 2, 3, and 4, respectively, relative to quartile 1. Associations between THMs and bladder cancer were stronger among subjects who were GSTT1 +/+ or +/− versus GSTT1 null (p_interaction = 0.021), GSTZ1 rs1046428 CT/TT versus CC (p_interaction = 0.018), or CYP2E1 rs2031920 CC versus CT/TT (p_interaction = 0.035). Among the 195 cases and 192 controls with high-risk forms of GSTT1 and GSTZ1, the ORs for quartiles 2, 3, and 4 of THMs were 1.5 (0.7–3.5), 3.4 (1.4–8.2), and 5.9 (1.8–19.0), respectively.

Conclusions

Polymorphisms in key metabolizing enzymes modified DBP-associated bladder cancer risk. The consistency of these findings with experimental observations of GSTT1, GSTZ1, and CYP2E1 activity strengthens the hypothesis that DBPs cause bladder cancer and suggests possible mechanisms as well as the classes of compounds likely to be implicated.     

Induction of blood lymphocyte cytochrome P450 2E1 in early stage alcoholic liver cirrhosis

To validate the induction of blood lymphocyte cytochrome P450 2E1 (CYP2E1) expression in alcoholic liver cirrhosis and mRNA and protein expression of CYP2E1 in freshly prepared blood lymphocytes of alcoholic liver cirrhotic (ACP), nonalcoholic cirrhotic patients (NACP), alcoholic controls (ACs), and nonalcoholic controls (NACs) were investigated. Registered ACP and NACP patients at Sanjay Gandhi Postgraduate Institute of Medical Science, Lucknow, India along with NACs and ACs were included in the study. Real time polymerase chain reaction, enzyme-linked immunosorbent assay, and CYP2E1-dependent enzyme activity were determined in blood lymphocytes isolated from cases and controls. Significant increases in CYP2E1 mRNA and protein expression were observed in freshly prepared blood lymphocytes isolated from ACs and ACP patients as compared with respective NACs or NACP patients. A concomitant increase in N-nitrosodimethyamine demethylase activity was evident in the blood lymphocytes of ACs and ACP patients. Interestingly, the comparative increase observed in CYP2E1 expression was of greater magnitude in the blood lymphocytes isolated from ACP patients, although they abstained from alcohol drinking. Findings suggest that significant increase in the CYP2E1 mRNA and protein expression in the blood lymphocytes, isolated from early stage ACP patients, can be used to predict alcohol-induced toxicity.     

Association of polymorphisms in nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4), mu-opioid receptor gene (OPRM1), and ethanol-metabolizing enzyme genes with alcoholism in Korean patients.

Findings obtained from several studies indicate that ethanol enhances the activity of alpha4beta2 neuronal nicotinic acetylcholine receptor and support the possibility that a polymorphism of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) modulates enhancement of nicotinic receptor function by ethanol. To identify the association between the CfoI polymorphism of the CHRNA4 and alcoholism, we examined distribution of genotypes and allele frequencies in Korean patients diagnosed with alcoholism (n = 127) and Korean control subjects without alcoholism (n = 185) with polymerase chain reaction-restriction fragment length polymorphism methods. We were able to detect the association between the CfoI polymorphism of the CHRNA4 and alcoholism in Korean patients (genotype P = .023; allele frequency P = .047). The genotypes and allele frequencies of known polymorphisms in other alcoholism candidate genes, such as alcohol metabolism-related genes [alcohol dehydrogenase 2 (ADH2), aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 3 (ADH3), and cytochrome P450 2E1 (CYP2E1)] and mu-opioid receptor gene (OPRM1), were studied. The polymorphisms of ADH2, ALDH2, and CYP2E1 were significantly different in Korean patients with alcoholism and Korean control subjects without alcoholism, but ADH3 and OPRM1 did not differ between the two groups.     

Sex-specific differences in the association of a common aldehyde dehydrogenase 2 gene polymorphism and alcohol consumption with stroke risk in a Korean population: a prospective cohort study

BACKGROUND/OBJECTIVESIt is well-known that alcohol consumption is associated with stroke risk as well as with aldehyde dehydrogenase 2 gene (ALDH2) polymorphisms. However, it is unclear whether ALDH2 polymorphisms are associated with stroke risk independent of alcohol consumption and whether such association is modified by sex. We evaluated sex-specific associations of a common ALDH2 polymorphism and alcohol consumption with stroke risk in a Korean population.SUBJECTS/METHODSWe conducted a prospective cohort study involving 8,465 men and women, aged 40-69 years and free of stroke between June, 2001 and January, 2003, and followed for the development of stroke. We identified new cases of stroke, which were self-reported or ascertained from vital registration data. Based on genome-wide association data, we selected a single-nucleotide polymorphism (rs2074356), which shows high linkage disequilibrium with the functional polymorphism of ALDH2. We conducted Cox proportional hazards regression analysis considering potential risk factors collected from a baseline questionnaire.RESULTSOver the median follow-up of 8 years, 121 cases of stroke were identified. Carrying the wild-type allele of the ALDH2 polymorphism increased stroke risk among men. The multivariate hazard ratio [95% confidence interval] of stroke was 2.02 [1.03-3.99] for the wild-type allele compared with the mutant alleles, but the association was attenuated after controlling for alcohol consumption. Combinations of the wild-type allele and other risk factors of stroke, such as old age, diabetes mellitus, and habitual snoring, synergistically increased the risk among men. Among women, however, the ALDH2 polymorphism was not associated with stroke risk.CONCLUSIONSThe prospective cohort study showed a significant association between a common ALDH2 polymorphism and stroke risk in Korean men, but not in Korean women, and also demonstrated that men with genetic disadvantages gain more risk when having risk factors of stroke. Thus, these men may need to make more concerted efforts to control modifiable risk factors of stroke.     

IL4R and IL13 polymorphic variants and development of antibodies to surface antigen of hepatitis B virus in hemodialysis patients in response to HBV vaccination or infection

We searched for an association between the interleukin 4 receptor gene (IL4R) rs1805015 and interleukin 13 gene (IL13) rs20541 polymorphisms and the development of antibodies to hepatitis B surface antigen (anti-HBs) in the case of hepatitis B virus (HBV) vaccination or infection in hemodialysis (HD) patients. HD patients who failed to respond to HBV vaccination did not differ in genotype frequencies of IL4R (TT 72.7%, CT 22.6%, CC 4.7%) and IL13 (CC 59.0%, CT 34.2%, TT 6.8%) from vaccine responders (IL4R TT 68.0%, CT 27.3%, CC 4.7%; IL13 CC 55.0%, CT 38.5%, TT 6.5%). HD patients who did not develop anti-HBs despite HBV infection also did not differ in genotype frequencies of IL4R (TT 67.8%, CT 26.8%, CC 5.4%) and IL13 (CC 60.7%, CT 33.9%, TT 5.4%) from HD patients who developed an anti-HBs response (IL4R TT 65.4%, CT 30.8%, CC 3.8%; IL13 CC 60.5%, CT 34.6%, TT 4.9%). In HD patients, neither the IL4R nor IL13 polymorphism is associated with anti-HBs development irrespective of whether an immunization is provoked by HBV vaccination or HBV infection.     

Are polymorphisms in metabolism protective or a risk for reduced white blood cell counts in a Chinese population with low occupational benzene exposures?

Background:

Genetic variations in metabolic enzyme genes may enhance hematotoxicity in benzene-exposed populations.

Objective:

To investigate the association between polymorphisms of metabolism genes and white blood cells (WBCs).

Methods:

Three hundred and eighty-five benzene-exposed workers and 220 unexposed indoor workers were recruited in China. We explored the relationship between metabolic enzymes polymorphisms [glutathione S-transferase T1/M1 (GSTT1/M1) null, glutathione S-transferase P1 (GSTP1)rs1695, Cytochrome P450 2E1 (CYP2E1) rs3813867, rs2031920, rs6413432, microsomal epoxide hydrolase (mEH) rs1051740, rs2234922] by polymerase chain reaction (PCR)–restriction fragment length polymorphism (RFLP) analysis and WBC.

Results:

The exposed group had lower WBC counts (P<0.001) than the unexposed group. Increased susceptibility to hematotoxicity, as evidenced by lower WBC counts, was found in workers with null-GSTT1 (P = 0.045), null-GSTM1 (P = 0.030), rs2031920 (P = 0.020), and rs3813867 (P = 0.014) genotypes. White blood cell counts were also lower in workers with null-GSTT1 and null-GSTM after adjusting for age, gender, smoking, and alcohol consumption.

Conclusion:

Null-GSTT1 and null-GSTM1 genotypes and Cytochrome P4502E1 (CYP2E1: rs2031920, rs3813867) may support the hematotoxicity of benzene-exposed workers in China, and we can make use of it to select susceptible population.     

细胞色素P450-2E1基因型对2-乙氧基乙醇代谢影响的研究

目的 探讨细胞色素P450－2E1（CYP2E1）不同基因型代谢2－乙氧基乙醇（EE）能力是否存在差异。方法 采用个体采样,毛细柱气相色谱分析技术及聚合酶链反应（PCR）检测方法,比较不同基因型个体累计接触EE剂量与2－乙在线性关系,B、C基因型回归系数大于A基因型。结论 CYP2E1B、C基因型代谢EE能力强于A基因型。     

Association of MDR1 and ERCC1 polymorphisms with response and toxicity to cisplatin-based chemotherapy in non-small-cell lung cancer patients

Among the cancer patient population, resistance to therapy is a major cause for therapeutic failure and for human sufferings, especially for the cancer with poor prognosis. Therefore, finding factors that contribute to drug resistance is a major research interest. In this study, we have investigated whether polymorphisms in genes that control import/export of drugs (MDR1) and that repair DNA adducts (ERCC1) are involved with drug resistance in non-small cell lung cancer (NSCLC) patients. We have recruited 95 patients with advanced NSCLC (stages IIIB-IV) who were specifically treated with platinum-based chemotherapy. We used the ligase detection reactions assay (LDR) to detect polymorphisms in ERCC1 118C/T, and MDR1 2677T/A, E1/-129T/C, and C3435T in peripheral blood lymphocytes from the patients. The haplotype of MDR1 gene single nucleotide polymorphisms (SNPs) were analyzed using the SHEsis software platform on line. We found that none of the single polymorphisms was associated with treatment response or related toxicity. However, patients carrying at least one variant MDR1 2677 T allele was associated with a significantly increased risk of drug resistance (OR=1.844, 95% CI=1.01-3.53, P=0.04) but also with a significantly increased risk of gastrointestinal toxicity (P=0.03) but not hemato-, hepato- or nephro-toxicities. Moreover, we analyzed the haplotypes of the three polymorphisms in MDR1. The patients harboring the E1/-129T-2677T-3435C haplotype had a significantly better response to chemotherapy compared with those having the other haplotypes (P=0.02, 95% CI=1.20-25.87), and a marginally significant association with increased risk of gastrointestinal toxicity (P=0.02, 95% CI=1.15-3.88). Our results suggested that gene polymorphisms in MDR1G2677T/A may be a predictive marker of platinum-based treatment response and of secondary effects, especially gastrointestinal toxicity for advanced NSCLC patients.     

RELATIONSHIP BETWEEN GENETIC POLYMORPHISM OF CYP2E1 AND ALDH2, AND POSSIBLE SUSCEPTIBILITY TO ALCOHOLISM

In 45 healthy Japanese volunteers, it was found that personsheterozygous for ALDH2 (ALDH2^*1/ALDH2^*2), and also either heterozygousor mutant homozygous for CYP2E1 (C₂/C₂ or C₁/C₂ can drink muchmore alcohol, even with (slight) flushing, than persons heterozygousfor ALDH2 (ALDH2^*1/ALDH2^*2) and normal homozygous for CYP2E1(C₁/C₁)     

Negative effects of serum p,p′-DDE on sperm parameters and modification by genetic polymorphisms

Objective

Effects of ambient exposure to DDT and its metabolites (DDE-DDT) on human sperm parameters and the role of genetic polymorphisms in modifying the association were investigated.

Methods

Demographics, medical history data, blood and semen samples were obtained from the first 336 male partners of couples presenting to 2 infertility clinics. Serum was analyzed for organochlorines (OC) and DNA for polymorphisms in GSTM1, GSTT1, GSTP1 and CYP1A1. Men with each sperm parameter considered low by WHO criteria (concentration <20 million/mL, motility <50%, morphology <4%) were compared to men with all normal sperm parameters in logistic regression models, controlling for sum of other OC pesticides.

Results

High DDE-DDT level was associated with significantly increased odds for all 3 low sperm parameters. The risk of low motility with high DDE-DDT exposure was increased in men with the GSTT1 null genotype compared to those with GSTT1 intact (odds ratio (OR)=4.19, 95% confidence interval (CI) 1.05-16.78 and OR=3.57, 1.43-8.93, respectively). Risk for low morphology in men with high DDE-DDT and one or both CYP1A1*2A alleles was lower compared to men with the common CYP1A1 alleles (OR=2.18, 0.78-6.07 vs. OR=3.45, 1.32-9.03, respectively). Similar results were obtained for men with low DDE-DDT exposure. Effects of high DDE-DDT on low sperm concentration (OR=2.53, 1.0-6.31) was unaffected by the presence of the polymorphisms.

Conclusion

High DDE-DDT exposure adversely affected all 3 sperm parameters and its effects were exacerbated by the GSTT1 null polymorphism and by the CYP1A1 common alleles.