Induction of rat liver microsomal epoxide hydrolase by thiazole and pyrazine: hydrolysis of 2-cyanoethylene oxide

Liver microsomal epoxide hydrolase (mEH) is active in the detoxificationof epoxide-containing carcinogens. The effects of thiazole andpyrazine, constituents of tobacco and tobacco smoke as wellas of a variety of foods, on the expression and regulation ofmEH were examined in rats (200 mg/kg body wt/day, i.p., 1/emdash3 days). Immunoblot analyses using rabbit anti-rat mEH antibodyrevealed a significant increase in mEH levels in hepatic microsomesisolated from either thiazole- or pyrazine-treated animals.Another protein (43 kd) cross-reacting with polyclonal mEH antibodywas found to be increased concomitantly following pyrazine treatment.Northern and slot blot analyses showed substantial increasesin mEH mRNA following either thiazole or pyrazine treatment.The level of mEH mRNA increased 17-fold at 24 h following thiazoletreatment, relative to control. Approximately 20- and 16-foldincreases in mEH mRNA were also observed at 48 and 72 h respectivelyfollowing treatment with pyrazine. The level of polymerase chainreaction (PCR)-amplified mEH DNA derived from poly(A)+ RNA wasclearly elevated following either thiazole or pyrazine treatmentrelative to that from untreated animals. Both sense and antisensestrands of PCR-amplified mEH DNA were cloned into an M13mpl9phage vector in order to examine the nucleotide sequences ofPCR-amplified mEH DNA derived from the poly(A)+ RNA isolatedfrom thiazole- or pyrazine-treated animals. Sequence analysesrevealed that the sequence of PCR-amplified DNA from the inducedmRNA was identical to that published for mEH cDNA. Epoxide hydrolaseactivity toward the hydrolysis of 2-cyanoethylene oxide (CEO),the epoxide metabolite of the rat carcinogen acrylonitrile,was not significant in hepatic microsomes from untreated rats,but was substantially induced by treatment with thiazole orpyrazine. Microsomal hydrolysis activity was heat-sensitiveand potently inhibited by l, l, l-trichloropropene-2, 3-oxide,indicating that mEH was the catalyst. The V_max for the hydrolysisof CEO by hepatic microsomes from thiazole-treated rats (13.4nmol/min/mg protein) was 1.5-fold greater than that with microsomesfrom pyrazine-treated rats, whereas similar K_m values ( 1 mM)were observed for both microsomal preparations. These kineticdata correlate well with the increases in mEH mRNA observedafter administration of thiazole or pyrazine to rats. Theseresults provide evidence that administration of thiazole orpyrazine induces mEH with a large increase in mEH mRNA, andthat the induced mEH catalyzes the hydrolysis of CEO.     

Functional polymorphisms of the microsomal epoxide hydrolase gene: a reappraisal on a early-onset lung cancer patients series

As concomitant chemoradiotherapy for stage III NSCLC is associated with survival advantage in comparison to a sequential approach, we conducted a phase III randomised study aiming to determine the best sequence and safety of chemotherapy (CT) and chemoradiotherapy (CT-RT), using a regimen with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR). Unresectable stage III NSCLC patients received CDDP (60 mg/m(2)), GEM (1g/m(2), days 1 and 8) and VNR (25mg/m(2), days 1 and 8) with reduced dosage of GEM and VNR during radiotherapy (66Gy). Two cycles of CT with radiotherapy followed by two further cycles of CT alone were administered in arm A or the reverse sequence in arm B. The study was prematurely closed for poor accrual due to administrative problems. Forty-nine eligible patients were randomised. Response rates and median survival times were, respectively 57% (95% CI: 36-78%) and 17 months (95% CI: 9.3-24.6 months) in arm A and 79% (95% CI: 64-94%) and 23.9 months (95% CI: 13.3-34.5 months) in arm B (p>0.05). Chemotherapy dose-intensity was significantly reduced in arm A. Grade 3-4 oesophagitis occurred in 5 patients. One case of grade 5 radiation pneumonitis was observed. In conclusion, chemoradiotherapy with CDDP, GEM and VNR appears feasible as initial treatment or after induction chemotherapy. Consolidation chemoradiotherapy seems less toxic with a better observed response rates and survival although no valid conclusion can be drawn from the comparison of both arms.     

Interindividual variations in the activities of cytosolic and microsomal epoxide hydrolase in human liver

Mammals have at least two epoxide hydrolases (EHs) with a broadsignificance in drug metabolism. One enzyme is localized inthe endoplasmic reticulum and other membranes (EH_m), and theother is in the cytosol (EH_c). In the present study we foundthat humans differ greatly in the activities of these enzymesin liver. The specific activities in microsomes from 166 subjects(most of them patients suffering from hepatic diseases), measuredwith benzo[]pyrene 4, 5-oxide as the substrate, varied by afactor of 63. The activities in the cytosol, determined withtrans-stilbene oxide as substrate varied 539-fold among 135subjects. A subdivision into different diagnostic groups showedan increase in EH_m activity (1.7-fold control) but not EH_c activityin tuberculosis patients treated with rifampicin, ethambutoland isoniazid. No other diagnostic group showed significantlyaltered EH activities. Furthermore the activities did not differbetween females and males, alcoholics and non-alcoholics orsmokers and non-smokers. In the 77 subjects where both EH_c andEH_m activities were determined, no correlation between themwas observed, indicating separate biological control.     

2,3-epoxy-4-hydroxynonanal, a potential lipid peroxidation product for etheno adduct formation, is not a substrate of human epoxide hydrolase

Our previous studies have shown that 2,3-epoxy-4-hydroxynonanal, a reactive epoxy aldehyde capable of forming etheno adducts with DNA bases, is mutagenic and tumorigenic (Carcinogenesis, 14, 2073). The epoxy aldehyde can be generated from trans-4-hydroxy-2-nonenal, a lipid peroxidation product of omega-6 polyunsaturated fatty acids, by autoxidation or by incubation with fatty acid hydroperoxides or hydrogen peroxides (Chem. Res. Toxicol., 9, 306). These are plausible in vivo pathways for the formation of 2,3-epoxy-4-hydroxynonanal. The possibility that 2,3-epoxy-4-hydroxynonanal is a tumorigen of endogenous origin is suggested by recent observations that etheno bases are detected as background DNA lesions in untreated rodents and humans. A metabolic pathway critical for detoxification of 2,3-epoxy-4- hydroxynonanal involves the ring-opening by epoxide hydrolase, which abolishes its ability to form cyclic etheno DNA adducts. In this study, we examined whether 2,3-epoxy-4-hydroxynonanal is a substrate of cDNA expressed human epoxide hydrolase. Human epoxide hydrolase was expressed in TK- 143 cells (thymidine kinase-deficient human embryoblast) infected with recombinant vaccinia virus encoding human epoxide hydrolase cDNA. Controls consisted of the cells infected with vaccinia virus in the absence of human epoxide hydrolase cDNA. No hydrolysis occurred when [2,3-(3)H]2,3-epoxy-4-hydroxynonanal was incubated at 37 degrees C for 30 min at pH 7.4 with cells expressing human epoxide hydrolase, as indicated by the presence of a pair of radioactive peaks in reversed-phase HPLC chromatography, which comigrated with the UV standards of the two diastereomers of the epoxy aldehyde. The identity of these compounds as the intact epoxy aldehyde was further supported by derivatization to the 2,4- dinitrophenylhydrazones followed by reversed phase HPLC analysis. Similar results were observed with the control cells or with the heat deactivated human epoxide hydrolase. The epoxide hydrolase activity in the expressed cells was demonstrated by their ability to convert benzo[a]pyrene-4,5-dihydroepoxide to benzo[a]pyrene-trans-4,5- dihydrodiol under the same conditions. These results clearly indicate that 2,3-epoxy-4-hydroxynonanal is not a substrate of human epoxide hydrolase, and, thus strengthen its possible endogenous role in the formation of promutagenic exocyclic etheno adducts in vivo.      

Detection of epoxide hydrolase in rat hepatoma cell lines and primary rat liver cells by immunoblotting

Rat epoxide hydrolase (EH) (EC 3.3.2.3) is elevated in cells of premalignant liver lesions, and variable EH activity has been reported for hepatocellular carcinomas. To facilitate detection of altered EH levels in liver cells, an immunoblotting method was devised. Rabbit antiserum specific for rat EH was prepared and used to detect EH extracted from suspensions of normal liver cells and from hepatoma cell lines. Compared with normal liver cells, 3 rat hepatoma cell lines, 7777, HTC and 17X, showed virtually undetectable EH levels by immunoblotting. The immunoblotting results rule out the possibility that very low EH enzymatic activity in the hepatoma cells results from production of normal amounts of non-functional enzyme protein.     

Alternative TrkAIII splicing: a potential regulated tumor-promoting switch and therapeutic target in neuroblastoma

An association between elevated tyrosine kinase receptor (Trk)-A expression and better prognosis; the absence of mutation-activated TrkA oncogenes; the induction of apoptosis, growth arrest, morphological differentiation and inhibition of xenograft growth; and angiogenesis by TrkA gene transduction, provide the basis for the current concept of an exclusively tumor-suppressor role for TrkA in the aggressive pediatric tumor, neuroblastoma. This concept, however, has recently been challenged by the discovery of a novel hypoxia-regulated alternative TrkAIII splice variant, initial data for which suggest predominant expression in advanced-stage neuroblastoma. TrkAIII exhibits neuroblastoma xenograft tumor-promoting activity associated with the induction of a more angiogenic and stress-resistant neuroblastoma phenotype and antagonises nerve growth factor/TrkAI antioncogenic signaling. In this short review, the authors integrate this novel information into a modified concept that places alternative TrkA splicing as a potential pivotal regulator of neuroblastoma behavior and identifies the TrkAIII alternative splice variant as a potential biomarker of patient prognosis and novel therapeutic target.     

High-activity microsomal epoxide hydrolase genotypes and the risk of oral, pharynx, and larynx cancers

Human microsomal epoxide hydrolase (mEH), encoded by the EPHX1 gene, is involved in the metabolism of tobacco carcinogens. We investigated the effect of exon 3 and 4 polymorphisms of the EPHX1 gene in 121 patients with cancers of the oral cavity/pharynx, 129 patients with cancer of the larynx, and 172 non-cancer controls, all Caucasian regular smokers. The potential modifying role of previously analyzed GSTM1, GSTM3, and GSTP1 genotypes was also examined. Compared with the putative low-activity genotypes, odds ratios (ORs) associated with predicted intermediate and high mEH activity genotypes were significantly increased for oropharyngeal cancers [OR = 1.8; 95% confidence interval (CI) = 1.0-3.3; and OR = 2.1; 95% CI = 1.0-4.5, respectively; P(trend) = 0.03] and laryngeal cancers (OR = 1.7; 95% CI = 1.0-3.1; and OR = 2.4; 95% CI = 1.1-5.1, respectively; P(trend) = 0.02). Moreover, a positive interaction was found between mEH activity and GSTM3 genotype for laryngeal cancer. The combined EPHX1 high activity-associated genotype and GSTM3 (AB or BB) genotype conferred a 13.1-fold risk (95% CI = 3.5-48.4) compared with the concurrent presence of the EPHX1 low activity-associated genotype and the GSTM3 AA genotype. Thus, EPHX1 polymorphisms may be one of the factors of importance in susceptibility to smoking-related cancers of the upper aerodigestive tract.     

Immunohistochemically demonstrated altered expression of cytochrome P-450 molecular forms and epoxide hydrolase in N-ethyl-N-hydroxyethylnitrosamine-induced rat kidney and liver lesions

A comparison of N-ethyl-N-hydroxyethylnistrosamine (EHEN)-inducedpreneoplastic and neoplastic lesions in the rat liver and kidneywas made with respect to the expression of different drug metabolizingenzymes. Four cytochrome P-450 species (cyt. P-450 UT₅₀, PB_3a,MC₁ and MC₂) and microsomal epoxide hydrolase (mEHb) were investigatedalong with two glutathione S-transferase species (GST-P andA forms) earlier shown to be elevated in putative preneoplasticlesions in the liver and kidney, respectively. In contrast tothe liver lesions, which showed clear decrease in all formsof cyt. P-450s and increase of mEHb, elevated levels of cyt.P-450 PB_3a and, to a lesser extent, the other P-450 forms andearly elevation to late decrease in mEHb characterized the renaltubular lesions. Thus opposite shift in enzyme phenotype wasobserved in carcinogen-induced focal lesions of the two organs.Variation in binding levels in the different nephron segmentsand zones of the liver acinus indicated physiological specializationwith regard to the enzymes investigated and suggested that thealtered phenotype of preneoplastic populations might be of adaptivesignificance.     

Microsomal epoxide hydrolase polymorphisms,cigarette smoking,and risk of colorectal cancer: The Fukuoka Colorectal Cancer Study

Microsomal epoxide hydrolase (EPHX1) plays an important role in the activation and detoxification of polycyclic aromatic hydrocarbons, carcinogens found in cigarette smoke. Polymorphisms in exon 3 (Y113H) and exon 4 (H139R) of the EPHX1 have been associated with enzyme activity. We investigated the risk of colorectal cancer in relation to the EPHX1 Y113H and H139R polymorphisms and assessed effect modifications of cigarette smoking and the other covariates. The interaction between the EPHX1 polymorphisms and selected genetic polymorphisms was also examined. We used data from Fukuoka Colorectal Cancer Study, a community‐based case–control study, including 685 cases and 778 controls. In‐person interviews were conducted to assess lifestyle factors. The EPHX1 Y113H and H139R polymorphisms were determined by the TaqMan assay and the polymerase chain reaction‐restriction fragment length polymorphism, respectively. Neither of the two polymorphisms nor the imputed EPHX1 phenotype was associated with colorectal cancer risk. Cigarette smoking and alcohol intake showed no effect modification on the association with the EPHX1 polymorphisms or the imputed EPHX1 phenotype. Increased risks of colorectal cancer associated with the 113Y allele and imputed EPHX1 phenotype were observed among individuals with high body mass index (BMI; ≥25.0 kg/m²), but not among those with low BMI (<25.0 kg/m²). The risk decreased with an increasing number of the 139R allele in the null genotypes of GSTM1/GSTT1. It is unlikely that the EPHX1 polymorphisms play an important role in colorectal carcinogenesis. The observed interactions of the EPHX1 polymorphisms with BMI and the GSTM1/GSTT1 genotypes warrant further investigation. © 2012 Wiley Periodicals, Inc.     

Microsomal epoxide hydrolase expression as a predictor of tamoxifen response in primary breast cancer: a retrospective exploratory study with long-term follow-up.

PURPOSE: It has been suggested that estrogen receptor-independent high-affinity binding sites for antiestrogens could limit their local bioavailability and response. Microsomal epoxide hydrolase (mEH) was recently shown to be a component of the antiestrogen binding site complex. We investigated whether mEH expression in primary breast tumors is related to disease outcome and to the efficacy of tamoxifen treatment. PATIENTS AND METHODS: Expression of mEH was semiquantitatively assessed by immunohistochemistry in sections prepared from archival paraffin blocks of primary breast cancers from 179 patients with a mean follow-up time of 81 months. RESULTS: Expression of mEH was correlated with poor disease outcome in all patients (P: < .01; n = 179) and in patients receiving tamoxifen (P: < .01; n = 78), but not in patients not treated with tamoxifen. Moreover, mEH was an independent prognostic factor by Cox regression analysis. CONCLUSION: The results of this first exploratory study suggest that mEH expression in primary breast cancer could be of predictive value for response to tamoxifen treatment and/or may be a novel independent prognostic factor for survival. The results are in agreement with the model that mEH participates in an estrogen receptor-independent tamoxifen- binding complex.     

Elevation of hepatic microsomal epoxide hydrolase activity by 2-acetylaminofluorene: strain and species differences

Hepatocarcinogens have been shown to cause marked elevationof hepatic microsomal epoxide hydrobase activity in the ratat short intervals after administration. The present studieswere designed to characterize 2-acetylaminofluorene (AAF) mediatedepoxide hydrolase elevation and to investigate the relationshipbetween epoxide hydrolase increases, AAF metabolism, and hepatocarcinogenicity.Oral or i.p. administration of AAF to F-344 rats produced log-lineardoseresponse curves for epoxide hydrolase elevation, measuredwith either benzo[a]pyrene-4, 5-oxide or styrene oxide substrate.Following a single dose of AAF (35 mg/kg), epoxide hydrolaseactivity was maximally increased (560% of control) within 48h, and the activity declined slowly, with a halflife of 17.5days. Co-treatment with actinomycin D effectively blocked theAAF dependent increase in epoxide hydrolase, suggesblng thatde novo protein synthesis is associated with the increase inenzyme activity. Dose-response curves for epoxide hydrolaseinduction by AAF, N-hydroxy-2-acetylaminofluorene (N-OH-AAF),and aminofluorene were compared, and the potencies for increasingepoxide hydrolase activity reflected the relative hepatocarcinogenicpotentials of these agents. In mice, which are resistant tothe hepatocarcinogenic action of AAF and deficient in AAF-N-hydroxylaseactivity, AAF caused no significant increase in hepatic microsomalepoxide hydrolase activity. Similarly, in Cotton rats and guineapigs, which are lacking in ability to form the sulfate conjugateof N-OH-AAF, neither i.p. nor dietary administration of AAFelicited increases in epoxide hydrolase activity at doses whichwere maximally effective in F-344 rats. These results supportthe hypothesis that the ability of compounds to increase epoxidehydrolase activity is related to their carcinogenic potency.Furthermore, the results suggest that increases in epoxide hydrolaseactivity are associated with metabolism of AAF to the putativeproximate carcinogen N-OH-AAF, and the subsequent conversionof this compound to the N-O-sulfate conjugate.     

微粒体过氧化物酶基因多态性与乳腺癌发生风险的Meta分析

目的:系统评价微粒体过氧化物酶基因(microsomal epoxide hydrolase,mEH)Tyr113His和His139Arg多态性与乳腺癌发病风险的关系.方法:计算机检索PubMed、EMBASE和Google学术数据库获得相关研究,提取数据资料后,对mEH多态性与乳腺癌易感性的相关性进行Meta分析,计算Odds ratios(ORs)及95%confidence intervals(CIs)评估上述两者相关性的强度.结果:共纳入7个研究,包括6357例病例和8090名对照.对等位基因对比模型(OR=0.99,95%CI=0.94~1.04,P=0.58)、显性基因模型(OR=1.14,95%CI=0.88~1.48,P=0.33)以及隐性基因模型(OR=1.03,95%CI=0.96~1.10,P=0.43)的分析发现mEH His等位基因与乳腺癌易感性风险没有显著相关性.同样,对等位基因对比模型(OR=0.97,95%CI=0.91~1.04,P=0.44)、显性基因模型(OR=1.01,95%CI=0.84~1.21,P=0.94)以及隐性基因模型(OR=1.04,95%CI=0.96~1.12,P=0.35)的分析发现mEH Arg等位基因与乳腺癌易感性风险没有显著相关性.而以种族为亚组分析显示这些基因多态性与乳腺癌易感性风险间也无显著相关性.结论:mEH Tyr113His和His139Arg多态性可能不是乳腺癌易感性风险的危险因素.     

Modulation of epidermal growth factor receptors in rat hepatocytes by two liver tumor-promoting regimens, a choline-deficient and a phenobarbital diet

The effect of two liver tumor-promoting regimens, a choline-deficient (CD) and a phenobarbital (.06% PB) diet, on the level of epidermal growth factor (EGF) receptor in rat hepatocytes was examined at 3, 10, and 28 days of feeding. Both diets produced a significant decrease in the number of cell surface receptors at 10 and 28 days of treatment. When PB was included in a CD diet, the decrease in the receptor number was evident even after 3 days feeding of the combined diet. Neither diet alone had any effect on the binding at that time. Along with the changes in the receptor number, the binding affinity of EGF to its receptor was also altered by these diets. Furthermore, PB and PB plus CD diets also decreased the EGF binding at the intracellular sites whereas CD diet showed no effects indicating that the decrease in surface binding of EGF by the promoter-treated hepatocytes was not due to rapid internalization of the receptors. The reduced level of hepatocyte surface EGF receptors represents the common property shared by two diverse types of the liver tumor promoters, and may thus be related to the tumor-promoting ability of these agents.     

The association of microsomal epoxide hydrolase polymorphisms and lung cancer risk in African-Americans and Mexican-Americans

This study evaluated the influence of genetic polymorphisms in the microsomal epoxide hydrolase (mEPHX) gene on lung cancer risk in a case-control study of two different ethnic groups, Mexican-Americans and African-Americans. There were 138 lung cancer cases (60 Mexican-American and 78 African-American) and 148 controls (76 Mexican-American and 72 African-American). There was a significant difference in the distribution of the mEPHX exon 4 polymorphism between the two ethnic groups with African-Americans more likely to be heterozygous and Mexican-Americans to be wild-type. There was no significant difference between the ethnic groups for the allelic distribution of the mEPHX exon 3 polymorphism. When the exon 4 and exon 3 polymorphism distributions in cases and controls were examined by ethnicity, only the Mexican-American cases showed a substantial proportion with the exon 4 polymorphism. The exon 4 polymorphism was associated with a significantly increased risk of lung cancer only among the Mexican-American cases (adjusted OR 3.6, 95% CI 1.26, 10.42). Younger Mexican-Americans with the exon 4 polymorphism had a greater risk of lung cancer than older members of their groups (adjusted OR 7.4, 95% CI 1.36, 40.23; 1.6, 95% CI 0.33, 7.80, respectively). The exon 3 polymorphism did not appear to significantly increase the risk of lung cancer in all but one study group examined. Mexican-Americans younger than 65 years did demonstrate an elevated risk of lung cancer (adjusted OR 4.6, 95% CI 1.19, 17.56). However, no statistically significant risk was observed in the African-American study groups for both exon 3 and exon 4 polymorphisms. These findings suggest that the presence of the exon 4 and exon 3 polymorphisms of mEPHX may be associated with an increased risk of lung cancer particularly among younger Mexican-Americans in this study.     

The association of weight gain during adulthood with prostate cancer incidence and survival: a population-based cohort

Obese men appear to have an increased risk of being diagnosed with advanced prostate cancer and of dying from the disease. Few studies have examined the impact of weight gain during adulthood on prostate cancer risk and mortality and these have reported conflicting results. We analysed data from 20,991 Norwegian men who participated in two phases of the Nord‐Trøndelag Health Study in 1984/1986 (HUNT‐1, when aged at least 20 years) and 1995/1997 (HUNT‐2). Weight and height were measured at both HUNT‐1 and HUNT‐2, allowing each man's change in weight and body mass index (BMI) to be computed. During a median of 9.3 years of follow‐up after the end of HUNT‐2, 649 (3%) men developed prostate cancer. We observed no increase in prostate cancer incidence amongst men who put on weight between HUNT‐1 and HUNT‐2. In multivariable models, including adjustment for weight at HUNT‐2, the hazard ratio (HR) for prostate cancer per one standard deviation, SD (6.2 kg) gain in weight was 0.98 (95% confidence interval [95% CI] = 0.87–1.10, p‐trend = 0.70) and per one SD gain in BMI (1.9 kg/m²) was 0.99 (95% CI = 0.90–1.10, p‐trend = 0.88). Amongst men diagnosed with prostate cancer (any stage), there was no evidence that gain in weight before diagnosis was positively associated with subsequent all‐cause mortality (HR per one SD increase in weight = 0.98; 95% CI = 0.81–1.19, p‐trend = 0.86). We conclude that weight gain in adulthood had no effect on prostate cancer incidence or survival in this population.     

Obesity,weight gain,and ovarian cancer risk in African American women

Although there is growing evidence that higher adiposity increases ovarian cancer risk, little is known about its impact in African American (AA) women, the racial/ethnic group with the highest prevalence of obesity. We evaluated the impact of body mass index (BMI) 1 year before diagnosis and weight gain since age 18 years on ovarian cancer risk in a population‐based case‐control study in AA women in 11 geographical areas in the US. Cases (n = 492) and age and site matched controls (n = 696) were identified through rapid case ascertainment and random‐digit‐dialing, respectively. Information was collected on demographic and lifestyle factors, including self‐reported height, weight at age 18 and weight 1 year before diagnosis/interview. Multivariable logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI), adjusting for potential covariates. Obese women had elevated ovarian cancer risk, particularly for BMI ≥ 40 kg/m² compared to BMI <25 (OR = 1.72, 95% CI: 1.12‐2.66; p for trend: 0.03). There was also a strong association with weight gain since age 18 (OR: 1.52; 95% CI: 1.07–2.16; p for trend: 0.02) comparing the highest to lowest quartile. In stratified analyses by menopausal status, the association with BMI and weight gain was limited to postmenopausal women, with a 15% (95% CI: 1.05–1.23) increase in risk per 5 kg/m² of BMI and 6% (95% CI: 1.01–1.10) increase in risk per 5 kg of weight gain. Excluding hormone therapy users essentially did not change results. Obesity and excessive adult weight gain may increase ovarian cancer risk in post‐menopausal AA women.     

Regulation of microsomal, xenobiotic epoxide hydrolase messenger RNA in persistent hepatocyte nodules and hepatomas induced by chemical carcinogens

We have utilized a DNA clone complementary to epoxide hydrolase mRNA as a probe to examine the level of the mRNA in persistent hepatocyte nodules and hepatomas induced by the Solt-Farber chemical carcinogenesis procedure. Epoxide hydrolase mRNA is increased 14-fold in nodules as compared to the level in normal liver. When rats with liver nodules were administered phenobarbital, an inducer of epoxide hydrolase mRNA in normal animals, a superinduction in epoxide hydrolase mRNA was observed in the nodules (22-fold) as compared to normal liver. Surprisingly, nodule induction in conjunction with phenobarbital administration also produced marked elevation in epoxide hydrolase mRNA levels in the tissue surrounding the nodules. Using HpaII and MspI to assess the degree of methylation of CCGG sites, we have found that the epoxide hydrolase gene is hypomethylated in nodules and hepatomas compared to the gene in normal liver tissue. Phenobarbital treatment alone increased epoxide hydrolase mRNA levels but did not result in hypomethylation of the epoxide hydrolase gene. These data further support the observation that hypomethylation of specific gene sequences occurs during chemical carcinogenesis and is correlated with an elevation in the steady state level of epoxide hydrolase mRNA in persistent hepatocyte nodules.     

Exposure to ethylene oxide in hospitals: biological monitoring and influence of glutathione S-transferase and epoxide hydrolase polymorphisms.

Ethylene oxide is considered as a human carcinogen. A biomarker of exposure would be a useful instrument to assess the risk in occupationally exposed workers. This cross-sectional study aimed at examining (a) whether the urinary excretion of a metabolite of ethylene oxide, 2-hydroxyethyl mercapturic acid (HEMA), could be used for monitoring occupational exposure and (b) whether glutathione S-transferase (GST) and epoxide hydrolase genotypes influenced biological monitoring. Exposure to ethylene oxide was measured by personal sampling in 80 hospital workers (95% of those eligible). HEMA concentrations were determined in three urine samples (baseline, end of shift, and next morning) by liquid chromatography with tandem mass spectrometry. GSTs (GSTT1, GSTM1, and GSTP1) and epoxide hydrolase (EPHX1) were also genotyped. The influence of exposure, genotypes, and several other factors was examined in multiple regression analyses. Exposure was always <1 parts per million. On a group basis, exposure and a non-null GSTT1 genotype increased the HEMA concentrations in the urine sample collected at the end of the shift and these factors remained statistically significant after considering possible confounding or modifying factors.