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Curtis J. Omiecinski - One of the best experts on this subject based on the ideXlab platform.

  • intronic dna elements regulate nrf2 chemical responsiveness of the human Microsomal Epoxide Hydrolase gene ephx1 through a far upstream alternative promoter
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Xi Yang, Curtis J. Omiecinski
    Abstract:

    In humans, Microsomal Epoxide Hydrolase (mEH) contributes important biological functions that underlie both detoxification and bioactivation fates arising from exposures to foreign chemicals. Previously, we discovered that human mEH gene transcription is initiated from alternative promoters. The respective transcripts are programmed with tissue specificity and the upstream E1b promoter contributes predominantly to mEH expression. The results presented demonstrate that exposures to the Nrf2 activators, sulforaphane (SFN) and tert-butylhydroquinone (tBHQ), markedly activate E1b transcription in human lung and liver cells. Genomic analyses identified two major DNase I hypersensitive regions (HS-1 and HS-2) within the ~15 kb intervening sequence separating E1b from the downstream E1 promoter. In BEAS-2B cells, the Nrf2 effectors, SFN and tBHQ, selectively activated the more distal HS-2 through an antioxidant response element (ARE). An activator protein 1/12-O-tetradecanoylphorbol-13-acetate interaction was further identified within the HS-2 enhancer that functioned to additionally contribute to ARE-mediated induction responsiveness of the E1b promoter. The results demonstrate that ARE modulation, integrated with additional transcriptional complexes, regulates the tissue-specific expression of mEH and that these processes likely coordinate both the protective and bioactivation functions contributed by mEH activities in human tissues.

  • the expression of human Microsomal Epoxide Hydrolase is predominantly driven by a genetically polymorphic far upstream promoter
    Journal of Pharmacology and Experimental Therapeutics, 2009
    Co-Authors: Xi Yang, Shun Hsin Liang, Denise M Weyant, Philip Lazarus, Carla J Gallagher, Curtis J. Omiecinski
    Abstract:

    Microsomal Epoxide Hydrolase (EPHX1) biotransforms Epoxide derivatives of pharmaceuticals, including metabolites of certain antiepileptic medications, such as phenytoin and carbamazepine, and many environmental Epoxides, such as those derived from butadiene, benzene, and carcinogenic polyaromatic hydrocarbons. We previously identified a far upstream promoter region, designated E1-b, in the EPHX1 gene that directs expression of an alternatively spliced EPHX1 mRNA transcript in human tissues. In this investigation, we characterized the structural features and expression character of the E1-b promoter region. Results of quantitative real-time polymerase chain reaction analyses demonstrated that the E1-b variant transcript is preferentially and broadly expressed in most tissues, such that it accounts for the majority of total EPHX1 transcript in vivo. Comparative genomic sequence comparisons indicated that the human EPHX1 E1-b gene regulatory region is primate-specific. Direct sequencing and genotyping approaches in 450 individuals demonstrated that the E1-b promoter region harbors a series of transposable element cassettes, including a polymorphic double Alu insertion. Results of reporter assays conducted in several human cell lines demonstrated that the inclusion of the Alu(+/+) insertion significantly decreases basal transcriptional activities. Furthermore, using haplotype block analyses, we determined that the E1-b polymorphic promoter region was not in linkage disequilibrium with two previously identified nonsynonomous single nucleotide polymorphisms (SNPs) in the coding region or with functional SNPs previously identified in the proximal promoter region of the gene. These results demonstrate that the upstream E1-b promoter is the major regulator of EPHX1 expression in human tissues and that polymorphism in this region may contribute an interindividual risk determinant to xenobiotic-induced toxicities.

  • alternative promoters determine tissue specific expression profiles of the human Microsomal Epoxide Hydrolase gene ephx1
    Molecular Pharmacology, 2005
    Co-Authors: Shun Hsin Liang, Christopher Hassett, Curtis J. Omiecinski
    Abstract:

    Microsomal Epoxide Hydrolase (EPHX1) catalyzes hydration reactions that determine the cellular disposition of reactive Epoxide derivatives. Whereas the previously defined EPHX1 exon 1 sequence (E1) is derived from a promoter proximal to exon 2 of the EPHX1 coding region, in this investigation, we identified an alternative EPHX1 exon 1 sequence, E1-b, originating from a gene promoter localized approximately 18.5 kb upstream of exon 2. Northern hybridizations demonstrated that the E1-b variant is widely expressed and that the E1-b promoter functions as the primary driver of EPHX1 expression in human tissues. In contrast, the E1 promoter directs expression only in the liver. To examine the basis for liver-specific usage of the E1 promoter, we identified several potential cis-regulatory elements that included GATA (-110/-105) and hepatocyte nuclear factor 3 (HNF3) (-96/-88) motifs. GATA-4 was the principal GATA family member interacting with its respective motif, whereas both HNF3alpha and HNF3beta were capable of interacting with the HNF3 element. GATA-4 and HNF3alpha/HNF3beta DNA binding complexes were enriched in hepatic cells. Site-directed mutagenesis and transactivation analyses of the E1 promoter revealed that GATA-4 is probably a principal factor that regulates liver-specific expression of the E1 variant, with HNF3alpha and HNF3beta acting to negatively regulate GATA-4 function in hepatic cells.

  • Functional analysis of human Microsomal Epoxide Hydrolase genetic variants
    Chemico-Biological Interactions, 2004
    Co-Authors: Vinayak Hosagrahara, Allan E. Rettie, Christopher Hassett, Curtis J. Omiecinski
    Abstract:

    Human Microsomal Epoxide Hydrolase (EPHX1) is active in the metabolism of many potentially carcinogenic or otherwise genotoxic Epoxides, such as those derived from the oxidation of polyaromatic hydrocarbons. EPHX1 is polymorphic and encodes allelic variation at least two amino acid positions, Y113H and H139R. In a number of recent molecular epidemiological investigations, EPHX1 polymorphism has been suggested as a susceptibility factor for several human diseases. To better evaluate the functional contribution of EPHX1 genetic polymorphism, we characterized the enzymatic properties associated with each of the respective variant proteins. Enzymatic profiles were evaluated with cis-stilbene oxide (cSO) and benzo[a]pyrene-4,5-Epoxide (BaPO), two prototypical substrates for the Hydrolase. In one series of experiments, activities of recombinant EPHX1 proteins were analyzed subsequent to their expression using the pFastbac® baculovirus vector in Spodoptera frugiperda-9 (Sf9) insect cells, and purification by column chromatography. In parallel studies, EPHX1 activities were evaluated with human liver microsomes derived from individuals of known EPHX1 genotype. Using the purified protein preparations, rates of cSO and BaPO hydrolysis for the reference protein, Y113/H139, were approximately 2-fold greater than those measured with the other EPHX1 allelic variants. However, when activities were analyzed using human liver Microsomal fractions, no major differences were evident in the reaction rates generated among preparations representing the different EPHX1 alleles. Collectively, these results suggest that the structural differences encoded by the Y113H and H139R variant alleles exert only modest impact on EPHX1-specific enzymatic activities in vivo.

  • fingerprinting of cytochrome p450 and Microsomal Epoxide Hydrolase gene expression in human blood cells
    Toxicological Sciences, 2000
    Co-Authors: Barbara C Krovat, Julia H Tracy, Curtis J. Omiecinski
    Abstract:

    To examine the character and variability of human cytochrome P450 (CYP) and Microsomal Epoxide Hydrolase (mEH) gene expression in human blood cells, we used a highly sensitive, quantitative, competitive reverse transcriptase-coupled polymerase chain reaction (QC RT-PCR) assay to assess mRNA profiles for a battery of 8 genes, in peripheral lymphocytes isolated from 10 healthy donors. Of the genes profiled, in lymphocytes CYP2D6 was typically expressed at the highest levels (3.8 x 10(5) molecules/microg total RNA), with CYP2E1 and mEH also maintained at relatively high abundance (1.2 x 10(5) and 1.8 x 10(5) molecules/microg total RNA, respectively). CYP1A1 levels were approximately an order of magnitude lower (3.9 x 10(4) molecules/microg total RNA), followed by CYP2F1 and CYP3A levels that were near the detection limit of the assay. CYP1A2 and CYP2A6/7 mRNAs were not detected in any of the lymphocyte samples. Overall, relatively low levels of inter-individual variation (2- to 6-fold) existed among these endpoint parameters in the subjects tested. To test whether established human blood cell lines were suitable models to assess basal expression and chemical induction responsiveness of these genes, we determined that constitutive CYP and mEH mRNA profiles were essentially conserved across 4 established human blood cell lines, and highly analogous to the basal expression patterns identified in freshly isolated peripheral lymphocytes. mEH protein was detected in all of the cell lines using Western immunoblotting and chemiluminescent visualization, whereas CYP1A1, CYP2D6, CYP2E1 or CYP3A proteins were not detected in these analyses. When blood cell-derived cultures were exposed to the prototypical CYP1A and CYP3A inducers, i.e., beta-naphthoflavone (beta-NF), dexamethasone (DEX) or phenobarbital, generally little or no inductive response was manifested. Thus, the data obtained from this investigation indicate that, although human blood cell lines in general exhibit poor responsiveness to prototypical inducer exposures, the constitutive patterns of CYP and mEH expression in peripheral lymphocytes appear to exhibit relatively low levels of variation among individuals. In addition, these in vivo patterns of expression are well maintained in established cultured blood-cell lines.

Christopher Hassett - One of the best experts on this subject based on the ideXlab platform.

  • alternative promoters determine tissue specific expression profiles of the human Microsomal Epoxide Hydrolase gene ephx1
    Molecular Pharmacology, 2005
    Co-Authors: Shun Hsin Liang, Christopher Hassett, Curtis J. Omiecinski
    Abstract:

    Microsomal Epoxide Hydrolase (EPHX1) catalyzes hydration reactions that determine the cellular disposition of reactive Epoxide derivatives. Whereas the previously defined EPHX1 exon 1 sequence (E1) is derived from a promoter proximal to exon 2 of the EPHX1 coding region, in this investigation, we identified an alternative EPHX1 exon 1 sequence, E1-b, originating from a gene promoter localized approximately 18.5 kb upstream of exon 2. Northern hybridizations demonstrated that the E1-b variant is widely expressed and that the E1-b promoter functions as the primary driver of EPHX1 expression in human tissues. In contrast, the E1 promoter directs expression only in the liver. To examine the basis for liver-specific usage of the E1 promoter, we identified several potential cis-regulatory elements that included GATA (-110/-105) and hepatocyte nuclear factor 3 (HNF3) (-96/-88) motifs. GATA-4 was the principal GATA family member interacting with its respective motif, whereas both HNF3alpha and HNF3beta were capable of interacting with the HNF3 element. GATA-4 and HNF3alpha/HNF3beta DNA binding complexes were enriched in hepatic cells. Site-directed mutagenesis and transactivation analyses of the E1 promoter revealed that GATA-4 is probably a principal factor that regulates liver-specific expression of the E1 variant, with HNF3alpha and HNF3beta acting to negatively regulate GATA-4 function in hepatic cells.

  • Functional analysis of human Microsomal Epoxide Hydrolase genetic variants
    Chemico-Biological Interactions, 2004
    Co-Authors: Vinayak Hosagrahara, Allan E. Rettie, Christopher Hassett, Curtis J. Omiecinski
    Abstract:

    Human Microsomal Epoxide Hydrolase (EPHX1) is active in the metabolism of many potentially carcinogenic or otherwise genotoxic Epoxides, such as those derived from the oxidation of polyaromatic hydrocarbons. EPHX1 is polymorphic and encodes allelic variation at least two amino acid positions, Y113H and H139R. In a number of recent molecular epidemiological investigations, EPHX1 polymorphism has been suggested as a susceptibility factor for several human diseases. To better evaluate the functional contribution of EPHX1 genetic polymorphism, we characterized the enzymatic properties associated with each of the respective variant proteins. Enzymatic profiles were evaluated with cis-stilbene oxide (cSO) and benzo[a]pyrene-4,5-Epoxide (BaPO), two prototypical substrates for the Hydrolase. In one series of experiments, activities of recombinant EPHX1 proteins were analyzed subsequent to their expression using the pFastbac® baculovirus vector in Spodoptera frugiperda-9 (Sf9) insect cells, and purification by column chromatography. In parallel studies, EPHX1 activities were evaluated with human liver microsomes derived from individuals of known EPHX1 genotype. Using the purified protein preparations, rates of cSO and BaPO hydrolysis for the reference protein, Y113/H139, were approximately 2-fold greater than those measured with the other EPHX1 allelic variants. However, when activities were analyzed using human liver Microsomal fractions, no major differences were evident in the reaction rates generated among preparations representing the different EPHX1 alleles. Collectively, these results suggest that the structural differences encoded by the Y113H and H139R variant alleles exert only modest impact on EPHX1-specific enzymatic activities in vivo.

  • post transcriptional regulation of human Microsomal Epoxide Hydrolase
    Pharmacogenetics, 1998
    Co-Authors: Elizabeth M Laurenzana, Christopher Hassett, Curtis J. Omiecinski
    Abstract:

    Microsomal Epoxide Hydrolase (mEH) is a key biotransformation enzyme that is variably expressed in humans. Genetic polymorphisms in the mEH gene have been identified that result in amino acid substitutions in the corresponding enzyme. Results of expression analyses of the mEH allelic variants in vitro suggest that the mutations do not affect the specific activity of the mEH enzyme, but may alter post-transcriptional regulation of mEH. To identify potential post-transcriptional mechanisms that influence mEH expression, the translational efficiency, mRNA half-life, and protein half-life of mEH allelic variants were determined. Constructs encoding each of the four mEH alleles were transcribed in vitro and translated. No differences were detected in the rate of protein synthesis among the variant transcripts, indicating that the previously characterized coding region polymorphisms do not appear to affect translational efficiency. mEH variant RNA half-lives were determined in transfected COS-1 cells, but no differences in decay rates were apparent among the polymorphic constructs. Half-lives of the polymorphic mEH proteins were determined in transiently transfected COS-1 cells treated with the protein synthesis inhibitor cycloheximide. Calculated protein half-lives were: Y113/H139, 15.2 h; H113/H139, 10.7 h, Y113/H139, 16.9 h and H113/R139, 16.0 h. The protein half-lives calculated for the polymorphic variants exhibited the same rank order as mEH protein and activity levels determined previously from expression experiments in vitro and therefore suggest that polymorphic amino acid substitution may result in altered protein stability. However, the differences noted were not statistically significant at the P < 0.05 level, and therefore additional study is required to firmly establish causative relationships.

  • human Microsomal Epoxide Hydrolase 5 flanking region genetic polymorphisms
    Carcinogenesis, 1998
    Co-Authors: S Raaka, Christopher Hassett, C J Omiencinski
    Abstract:

    Microsomal Epoxide Hydrolase (mEH) catalyses the hydrolysis of xenobiotic Epoxides, including various Epoxide derivatives of the procarcinogenic polyaromatic hydrocarbons. Levels of mEH enzymatic activity among different cell types and between individuals within the population vary considerably. Genetic polymorphisms within the structural region of the human mEH gene exist and appear to contribute to the population variance in functional expression. In this study, we used single strand conformational polymorphism analysis and direct DNA sequencing approaches to identify seven additional polymorphic sites within the upstream region of the mEH gene, spanning ‐ 743 to F185 bp, relative to the transcription initiation site. Allelic frequencies and linkages of the polymorphic nucleotides were determined in 51 individuals using restriction fragment length polymorphism or competitive oligonucleotide priming assays. To determine the functional significance of the individual nucleotide substitutions, DNA fragments representing the variant alleles were cloned into the heterologous pBRAMScat2 reporter vector, transfected into HepG2 cells and assessed for reporter gene expression. Results indicated that certain of these polymorphic loci might differentially regulate transcription, with the maximum contribution of any of the variants modifying levels of reporter gene activity by ~ 30%. These observations establish that genetic variation in the 59 flanking sequence of mEH gene is likely an additional contributing factor to the range of functional mEH expression existing in human populations.

  • human hepatic Microsomal Epoxide Hydrolase comparative analysis of polymorphic expression
    Archives of Biochemistry and Biophysics, 1997
    Co-Authors: Christopher Hassett, Elizabeth M Laurenzana, Jing Lin, Cara L Carty, Curtis J. Omiecinski
    Abstract:

    Interindividual variation in the expression of human Microsomal Epoxide Hydrolase (mEH) may be an important risk factor for chemically induced toxicities, including cancer and teratogenesis. In this study, phenotypic variability and mEH genetic polymorphisms were examined in a bank of 40 transplant-quality human liver samples. Immunochemically determined protein content, enzymatic activities, polymorphic amino acids, as well as mEH RNA levels were evaluated in parallel. Enzymatic activity was assessed using (+/-)-benzo[a]pyrene-4,5-Epoxide at 2 substrate concentrations. The relative hydrolyzing activities obtained using saturating substrate levels were highly correlated (r = 0.85) with results derived from limiting substrate concentrations and exhibit approximately an 8-fold range in activity levels across the panel of 40 liver samples. mEH enzyme activity also demonstrated strong correlation (r > or = 0.74) with an 8.4-fold variation determined for mEH protein content within the same samples. However, these protein/activity measurements were poorly correlated (r < or = 0.23) with mEH RNA levels, which exhibited a 49-fold variation. Two common polymorphic amino acid loci in the mEH protein did not exclusively account for variation in enzymatic activity, although this conclusion is confounded by heterozygousity in the samples. These data demonstrate the extent of hepatic mEH functional variability in well-preserved human tissues and suggest that polymorphism of mEH protein expression is regulated in part by posttranscriptional controls, which may include nonstructural regulatory regions of the mEH transcript.

David C Christiani - One of the best experts on this subject based on the ideXlab platform.

  • Genetic Polymorphisms in N-acetyltransferase-2 and Microsomal Epoxide Hydrolase, Cumulative Cigarette Smoking,
    2016
    Co-Authors: Lung Cancer, Wei Zhou, Geoffrey Liu, Sally W. Thurston, David P. Miller, John C. Wain, Thomas J. Lynch, David C Christiani
    Abstract:

    N-acetyltrasferase-2 (NAT2) and Microsomal Epoxide Hydrolase (mEH) are polymorphic genes that metabolize different tobacco carcinogens. Smaller studies found inconsistent relationships between NAT2 or mEH polymorphisms and lung cancer risk. To determine whether there is gene-environment interaction between NAT2 polymorphisms, alone or in combination with mEH polymorphisms, and cumulative smoking exposure in the development of lung cancer, we conducted a case control study of 1115 Caucasian lung cancer patients and 1250 spouse and friend controls. The results were analyzed using generalized additive models and logistic regression, adjusting for relevant covariates. There was no overall relationship between NAT2 genotype and lung cance

  • Microsomal Epoxide Hydrolase endotoxin and lung function decline in cotton textile workers
    American Journal of Respiratory and Critical Care Medicine, 2005
    Co-Authors: Jingqing Hang, Xiaorong Wang, Hongxi Zhang, Bixiong Sun, Helian Dai, Wei Zhou, David C Christiani
    Abstract:

    Occupational exposure to endotoxin in organic dust may induce lung function decline. Microsomal Epoxide Hydrolase (mEH) detoxifies reactive oxygen species generated by endotoxin exposure, and polymorphisms of the mEH gene are associated with altered enzyme activity. We investigated the associations between mEH polymorphisms, endotoxin exposure, and lung function decline in a 20-year prospective study of 265 workers exposed to endotoxin and 234 control subjects. mEH Tyr113His and His139Arg polymorphisms were genotyped by the 5′ nuclease assay, and data were analyzed using multivariate linear regression models, adjusting for important covariates. Overall, the annual decline rate of FEV1 was 29.47 ml during the 20-year follow-up. Endotoxin exposure was associated with faster lung function decline among genotypes associated with slower enzyme activity: estimates (SE) of annual FEV1 decline rates for endotoxin exposure were −2.33 (2.07), −2.81 (1.66), and −6.73 (2.83) ml for Tyr/Tyr, Tyr/His, and His/His genot...

  • genetic polymorphisms in n acetyltransferase 2 and Microsomal Epoxide Hydrolase cumulative cigarette smoking and lung cancer
    Cancer Epidemiology Biomarkers & Prevention, 2002
    Co-Authors: Wei Zhou, Geoffrey Liu, Sally W. Thurston, David P. Miller, John C. Wain, Thomas J. Lynch, David C Christiani
    Abstract:

    N -acetyltrasferase-2 ( NAT2 ) and Microsomal Epoxide Hydrolase ( mEH ) are polymorphic genes that metabolize different tobacco carcinogens. Smaller studies found inconsistent relationships between NAT2 or mEH polymorphisms and lung cancer risk. To determine whether there is gene-environment interaction between NAT2 polymorphisms, alone or in combination with mEH polymorphisms, and cumulative smoking exposure in the development of lung cancer, we conducted a case control study of 1115 Caucasian lung cancer patients and 1250 spouse and friend controls. The results were analyzed using generalized additive models and logistic regression, adjusting for relevant covariates. There was no overall relationship between NAT2 genotype and lung cancer risk; the adjusted odds ratio (OR) of the rapid versus slow acetylator genotypes was 0.96 [95% confidence interval (CI), 0.79–1.16]. However, gene-environment interaction analyses revealed that the adjusted ORs increased significantly as pack-years increased. For nonsmokers, the fitted OR was 0.66 (95% CI, 0.44–0.99), whereas for heavy smokers (80 pack-years), the OR increased to 1.22 (95% CI, 0.89–1.67). When comparing the extreme genotype combinations of the NAT2 rapid acetylator, higher mEH activity genotype to the NAT2 slow acetylator, and very low mEH activity genotype, the corresponding ORs at 0 and 80 pack-years were 0.30 (95% CI, 0.14–0.62) and 2.19 (95% CI, 1.26–3.81), respectively. Results were similar with ORs derived from stratified models. In conclusion, NAT2 rapid acetylator genotypes are protective against lung cancer in nonsmokers but are risk factors in heavy smokers. The joint effects of NAT2 and mEH polymorphisms are consistent with an independent, additive effect of these two genes, modified by smoking history.

  • the interaction between Microsomal Epoxide Hydrolase polymorphisms and cumulative cigarette smoking in different histological subtypes of lung cancer
    Cancer Epidemiology Biomarkers & Prevention, 2001
    Co-Authors: Wei Zhou, Geoffrey Liu, Sally W. Thurston, David P. Miller, John C. Wain, Thomas J. Lynch, David C Christiani
    Abstract:

    Microsomal Epoxide Hydrolase (mEH) is involved in the metabolism of environmental and tobacco carcinogens. Smaller studies found inconsistent results in the relationship between mEH polymorphisms and lung cancer risk. We investigated the two polymorphisms of mEH in 974 Caucasian lung cancer patients and 1142 controls using PCR-RFLP techniques. The results were analyzed using generalized additive models and logistic regression, adjusting for relevant covariates. There was no overall relationship between mEH genotypes and lung cancer risk. The adjusted odds ratio (OR) of the very low activity genotype versus that of other genotypes combined was 1.00 [95% confidence interval (CI), 0.74-1.34]. However, gene-environment interaction analyses revealed that the ORs decreased as cumulative smoking (defined as square root of pack-years) increased. When pack-years = 0, the OR was 1.89 (95% CI, 1.08-3.28). When pack-years = 28.5, the OR was 1.00 (95% CI, 0.76-1.32), and when pack-years = 80, the OR decreased to 0.65 (95% CI, 0.42-1.00). When cases were stratified according to histological subtypes, the interaction between mEH genotype and cumulative smoking was statistically significant (P < 0.01) for the 222 squamous cell carcinoma cases, whereas it was not significant (P = 0.18) for the 432 adenocarcinoma cases. In conclusion, cumulative cigarette smoking plays a pivotal role in the association between mEH polymorphisms and lung cancer risk, altering the direction of risk (in the case of the very low activity genotype) from a risk factor in nonsmokers to a relatively protective factor in heavy smokers.

Karen W Makar - One of the best experts on this subject based on the ideXlab platform.

  • colorectal polyp type and the association with charred meat consumption smoking and Microsomal Epoxide Hydrolase polymorphisms
    Nutrition and Cancer, 2011
    Co-Authors: Andrea N Burnetthartman, Margaret T Mandelson, Scott V Adams, Karen J Wernli, Mazyar Shadman, Michelle A Wurscher, Polly A. Newcomb, Karen W Makar
    Abstract:

    We determined the association between charred meat consumption, cigarette smoking, Microsomal Epoxide Hydrolase (mEH) polymorphisms (rs1051740 and rs2234922), and colorectal adenomas and hyperplastic polyps (HPs) and explored gene–environment interactions. Men and women with colorectal adenomas (n = 519), HPs (n = 691), or concurrently with both types of polyps (n = 227) and polyp-free controls (n = 772) receiving a colonoscopy from December 2004 to September 2007 were recruited. Participants completed telephone interviews and provided buccal cell samples; genotyping of mEH was completed using Taqman assays. We conducted polytomous regression and calculated odd ratios (OR) and 95% confidence intervals. Interactions were evaluated using Wald chi-square tests. Consumption of >3 servings of charred meat per week was associated with distal HPs (OR = 2.0, 1.2–3.4) but not adenomas nor either type of proximal polyp. Heavy cigarette smoking (≥ 22 pack-years) was associated with an increased risk for colorectal a...

  • colorectal polyp type and the association with charred meat consumption smoking and Microsomal Epoxide Hydrolase polymorphisms
    Nutrition and Cancer, 2011
    Co-Authors: Andrea N Burnetthartman, Margaret T Mandelson, Scott V Adams, Karen J Wernli, Mazyar Shadman, Michelle A Wurscher, Polly A. Newcomb, Karen W Makar
    Abstract:

    We determined the association between charred meat consumption, cigarette smoking, Microsomal Epoxide Hydrolase (mEH) polymorphisms (rs1051740 and rs2234922), and colorectal adenomas and hyperplastic polyps (HPs) and explored gene-environment interactions. Men and women with colorectal adenomas (n = 519), HPs (n = 691), or concurrently with both types of polyps (n = 227) and polyp-free controls (n = 772) receiving a colonoscopy from December 2004 to September 2007 were recruited. Participants completed telephone interviews and provided buccal cell samples; genotyping of mEH was completed using Taqman assays. We conducted polytomous regression and calculated odd ratios (OR) and 95% confidence intervals. Interactions were evaluated using Wald chi-square tests. Consumption of >3 servings of charred meat per week was associated with distal HPs (OR = 2.0, 1.2-3.4) but not adenomas nor either type of proximal polyp. Heavy cigarette smoking (≥ 22 pack-years) was associated with an increased risk for colorectal adenomas (OR = 1.7, 95% CI: 1.2-2.4), HPs (OR = 2.4, 95% CI: 1.7-3.3), and both types (OR = 2.8, 95% CI: 1.8-4.3) with the strongest association for distal polyps. There was no association between mEH genotype and colorectal polyps, nor were any statistically significant gene-environment interactions identified. Future investigation of BaP exposure and colorectal neoplasia should analyze whether associations are dependent upon anatomic location.

Wei Zhou - One of the best experts on this subject based on the ideXlab platform.

  • Genetic Polymorphisms in N-acetyltransferase-2 and Microsomal Epoxide Hydrolase, Cumulative Cigarette Smoking,
    2016
    Co-Authors: Lung Cancer, Wei Zhou, Geoffrey Liu, Sally W. Thurston, David P. Miller, John C. Wain, Thomas J. Lynch, David C Christiani
    Abstract:

    N-acetyltrasferase-2 (NAT2) and Microsomal Epoxide Hydrolase (mEH) are polymorphic genes that metabolize different tobacco carcinogens. Smaller studies found inconsistent relationships between NAT2 or mEH polymorphisms and lung cancer risk. To determine whether there is gene-environment interaction between NAT2 polymorphisms, alone or in combination with mEH polymorphisms, and cumulative smoking exposure in the development of lung cancer, we conducted a case control study of 1115 Caucasian lung cancer patients and 1250 spouse and friend controls. The results were analyzed using generalized additive models and logistic regression, adjusting for relevant covariates. There was no overall relationship between NAT2 genotype and lung cance

  • Microsomal Epoxide Hydrolase endotoxin and lung function decline in cotton textile workers
    American Journal of Respiratory and Critical Care Medicine, 2005
    Co-Authors: Jingqing Hang, Xiaorong Wang, Hongxi Zhang, Bixiong Sun, Helian Dai, Wei Zhou, David C Christiani
    Abstract:

    Occupational exposure to endotoxin in organic dust may induce lung function decline. Microsomal Epoxide Hydrolase (mEH) detoxifies reactive oxygen species generated by endotoxin exposure, and polymorphisms of the mEH gene are associated with altered enzyme activity. We investigated the associations between mEH polymorphisms, endotoxin exposure, and lung function decline in a 20-year prospective study of 265 workers exposed to endotoxin and 234 control subjects. mEH Tyr113His and His139Arg polymorphisms were genotyped by the 5′ nuclease assay, and data were analyzed using multivariate linear regression models, adjusting for important covariates. Overall, the annual decline rate of FEV1 was 29.47 ml during the 20-year follow-up. Endotoxin exposure was associated with faster lung function decline among genotypes associated with slower enzyme activity: estimates (SE) of annual FEV1 decline rates for endotoxin exposure were −2.33 (2.07), −2.81 (1.66), and −6.73 (2.83) ml for Tyr/Tyr, Tyr/His, and His/His genot...

  • genetic polymorphisms in n acetyltransferase 2 and Microsomal Epoxide Hydrolase cumulative cigarette smoking and lung cancer
    Cancer Epidemiology Biomarkers & Prevention, 2002
    Co-Authors: Wei Zhou, Geoffrey Liu, Sally W. Thurston, David P. Miller, John C. Wain, Thomas J. Lynch, David C Christiani
    Abstract:

    N -acetyltrasferase-2 ( NAT2 ) and Microsomal Epoxide Hydrolase ( mEH ) are polymorphic genes that metabolize different tobacco carcinogens. Smaller studies found inconsistent relationships between NAT2 or mEH polymorphisms and lung cancer risk. To determine whether there is gene-environment interaction between NAT2 polymorphisms, alone or in combination with mEH polymorphisms, and cumulative smoking exposure in the development of lung cancer, we conducted a case control study of 1115 Caucasian lung cancer patients and 1250 spouse and friend controls. The results were analyzed using generalized additive models and logistic regression, adjusting for relevant covariates. There was no overall relationship between NAT2 genotype and lung cancer risk; the adjusted odds ratio (OR) of the rapid versus slow acetylator genotypes was 0.96 [95% confidence interval (CI), 0.79–1.16]. However, gene-environment interaction analyses revealed that the adjusted ORs increased significantly as pack-years increased. For nonsmokers, the fitted OR was 0.66 (95% CI, 0.44–0.99), whereas for heavy smokers (80 pack-years), the OR increased to 1.22 (95% CI, 0.89–1.67). When comparing the extreme genotype combinations of the NAT2 rapid acetylator, higher mEH activity genotype to the NAT2 slow acetylator, and very low mEH activity genotype, the corresponding ORs at 0 and 80 pack-years were 0.30 (95% CI, 0.14–0.62) and 2.19 (95% CI, 1.26–3.81), respectively. Results were similar with ORs derived from stratified models. In conclusion, NAT2 rapid acetylator genotypes are protective against lung cancer in nonsmokers but are risk factors in heavy smokers. The joint effects of NAT2 and mEH polymorphisms are consistent with an independent, additive effect of these two genes, modified by smoking history.

  • the interaction between Microsomal Epoxide Hydrolase polymorphisms and cumulative cigarette smoking in different histological subtypes of lung cancer
    Cancer Epidemiology Biomarkers & Prevention, 2001
    Co-Authors: Wei Zhou, Geoffrey Liu, Sally W. Thurston, David P. Miller, John C. Wain, Thomas J. Lynch, David C Christiani
    Abstract:

    Microsomal Epoxide Hydrolase (mEH) is involved in the metabolism of environmental and tobacco carcinogens. Smaller studies found inconsistent results in the relationship between mEH polymorphisms and lung cancer risk. We investigated the two polymorphisms of mEH in 974 Caucasian lung cancer patients and 1142 controls using PCR-RFLP techniques. The results were analyzed using generalized additive models and logistic regression, adjusting for relevant covariates. There was no overall relationship between mEH genotypes and lung cancer risk. The adjusted odds ratio (OR) of the very low activity genotype versus that of other genotypes combined was 1.00 [95% confidence interval (CI), 0.74-1.34]. However, gene-environment interaction analyses revealed that the ORs decreased as cumulative smoking (defined as square root of pack-years) increased. When pack-years = 0, the OR was 1.89 (95% CI, 1.08-3.28). When pack-years = 28.5, the OR was 1.00 (95% CI, 0.76-1.32), and when pack-years = 80, the OR decreased to 0.65 (95% CI, 0.42-1.00). When cases were stratified according to histological subtypes, the interaction between mEH genotype and cumulative smoking was statistically significant (P < 0.01) for the 222 squamous cell carcinoma cases, whereas it was not significant (P = 0.18) for the 432 adenocarcinoma cases. In conclusion, cumulative cigarette smoking plays a pivotal role in the association between mEH polymorphisms and lung cancer risk, altering the direction of risk (in the case of the very low activity genotype) from a risk factor in nonsmokers to a relatively protective factor in heavy smokers.