Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of organosulfur compounds were synthesized with the aim of developing chemopreventive compounds active against hepatotoxicity and chemical carcinogenesis. 2-(Allylthio) pyrazine (2-AP) was effective in inhibiting cytochrome P450 2E1-mediated catalytic activities and protein expression, and in inducing microsomal epoxide hydrolase and major glutathione S-transferases. 2-AP reduced the hepatotoxicity caused by toxicants and elevated cellular GSH content. Development of skin tumors, pulmonary adenoma and aberrant crypt foci in colon by various chemical carcinogens was inhibited by 2-AP pretreatment. Anticarcinogenic effects of 2-AP at the stage of initiation of tumors were also observed in the aflatoxin B1 (AFB1)-induced three-step medium-term hepatocarcinogenesis model. Reduction of AFB1-DNA adduct by 2-AP appeared to result from the decreased formation of AFB1-8,9-epoxide via suppression of cytochrome P450, while induction of GST by 2-AP increases the excretion of glutathione-conjugated AFB1. 2-AP was a radioprotective agent effective against the lethal dose of total body irradiation and reduced radiation-induced injury in association with the elevation of detoxifying gene expression. 2-AP produces reactive oxygen species in vivo, which is not mediated with the thiol-dependent production of oxidants and that NF-kappa B activation is not involved in the induction of the detoxifying enzymes. The mechanism of chemoprotection by 2-AP may involve inhibition of the P450-mediated metabolic activation of chemical carcinogens and enhancement of electrophilic detoxification through induction of phase II detoxification enzymes which would facilitate the clearance of activated metabolites through conjugation reaction.
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PMID:Chemopreventive effects of 2-(allylthio)pyrazine. 1023 Apr 97

We estimated associations between polymorphisms in the gene encoding microsomal epoxide hydrolase (mEH) among 464 cases diagnosed with first occurrence of colorectal adenoma and 510 matched controls. In an analysis controlling only for the matching variables, we found little or no association between adenoma and mEH genotypes defined by polymorphisms at either codon 113 and 139 or mEH activity predicted by both polymorphisms. However, in subsequent analyses, high predicted mEH activity was significantly associated with adenoma among certain subgroups defined by smoking history [odds ratio (OR), 4.27; 95% confidence interval (CI), 1.68-10.81 among current smokers; interaction, P = 0.11], meat consumption (OR, 2.47; CI, 0.99-6.19 among individuals who regularly eat well-done meat; interaction, P = 0.03), and genotypes for the *A/*B polymorphism in the gene encoding glutatione S-transferase M3 (OR, 2.60; CI, 1.28-5.28 among individuals with *A*A genotype; interaction, P = 0.03). These findings are consistent with causal roles for environmental polycyclic aromatic hydrocarbons and genetically encoded variants in enzymes whose actions lead to the production of activated polycyclic aromatic hydrocarbon metabolites.
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PMID:A case-control study of microsomal epoxide hydrolase, smoking, meat consumption, glutathione S-transferase M3, and risk of colorectal adenomas. 1128

Microsomal epoxide hydrolase (mEH) metabolizes polycyclic aromatic hydrocarbons, carcinogens found in cigarette smoke and cooked meat. Polymorphisms in exon 3 and exon 4 of the mEH gene have been found to alter mEH activity. We investigated the association between these polymorphisms and colorectal polyps within the Minnesota Cancer Prevention Research Unit case-control study. Cases were diagnosed with colonoscopically confirmed adenomas (n = 530) or hyperplastic polyps (n = 202); controls (n = 649) were polyp-free at colonoscopy. Smoking history and meat consumption were obtained from self-administered questionnaires before colonoscopy. mEH genotypes were determined by PCR/RFLP or oligonucleotide ligation assay. The overall risks associated with exon 3 or exon 4 polymorphisms for both adenomas and hyperplastic polyps were not statistically different from 1.0. Compared with exon 3 Tyr/Tyr, 0 pack-years, risk was highest among those with the exon 3 His/His genotype and >25 pack-years of smoking [adenoma, odds ratio (OR) = 4.9 (1.9-12.8); hyperplastic, OR = 7.7 (2.5-24.0)]. Risks were not elevated among exon 4 homozygous variants, even in the presence of heavy smoking. Fried, baked, or broiled meat intake of > or =two servings/week (high) compared with < or =one serving/week was associated with a 2-fold increase in risk of adenoma. The highest risks were seen for those with the exon 3 His/His genotype and high cooked meat intake [OR = 3.3 (1.4-7.9); reference group: Tyr/Tyr, < or = 1 serving/week). Although mEH polymorphisms are not associated with an increased risk of colorectal polyps overall, genotypes that produce a slow phenotype appear to be associated with an increased risk in the presence of smoking and high intakes of cooked meat.
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PMID:Epoxide hydrolase Tyr113His polymorphism is associated with elevated risk of colorectal polyps in the presence of smoking and high meat intake. 1148 54

Microsomal epoxide hydrolase (mEH) is involved in the bioactivation and detoxification of polycyclic aromatic hydrocarbons derived from tobacco smoke and charred meat intake. Two coding region mEH variants located in exon 3 (Tyr113His) and exon 4 (His139Arg) have been described and may affect the enzyme's specific activity. We investigated these polymorphisms and tested interactions with smoking and charred meat intake in relation to risk of colorectal adenoma in two case-control studies nested in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts. mEH exon 3 and exon 4 polymorphisms were not associated with overall risk of adenoma among 556 incident cases and 557 controls from the NHS or 376 prevalent cases and 725 controls from the HPFS. A statistically significant interaction was found between the exon 4 polymorphism and smoking for men (P = 0.03) and a borderline significant interaction was found between the exon 3 polymorphism and smoking for women (P = 0.06). Women having the exon 3 'rapid' Tyr/Tyr genotype were at increased risk when exposed to either > or =25 pack-years smoking [relative risk (RR) = 2.43, 95% confidence interval (CI) 1.47-4.01] or <25 pack-years of smoking (RR = 1.73, 95% CI 1.10-2.73) relative to non-smokers. Men with the exon 4 'slow' His/His genotype were at increased risk when exposed to > or =25 pack-years smoking (RR = 2.21, 95% CI 1.43, 3.41) or <25 pack-years smoking (RR = 1.71, 95% CI 1.13-2.59) relative to non-smokers. Charred meat intake was not associated with adenoma risk and there was no significant interaction with either mEH polymorphism. Our results indicate that individuals exposed to > or =25 pack-years smoking were at increased risk for colorectal adenoma and that risk is related to dose of tobacco carcinogens and mEH activity level, but the results were not consistent between men and women.
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PMID:Epoxide hydrolase polymorphisms, cigarette smoking and risk of colorectal adenoma in the Nurses' Health Study and the Health Professionals Follow-up Study. 1498 21

Cigarette smoking is a risk factor for colorectal adenoma, a precursor of colorectal cancer. Microsomal epoxide hydrolase (EPHX1) metabolizes polycyclic aromatic hydrocarbons, carcinogens found in cigarette smoke. Nonsynonymous variants of EPHX1 at Tyr(113)His (exon 3) and His(139)Arg (exon 4) are associated, respectively, with low ((113)His) and high ((139)Arg) predicted activity. Among participants randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we evaluated risks for advanced adenoma in relation to cigarette use and these two EPHX1 variants. We compared 772 cases with advanced adenoma (adenoma >/=1 cm or containing high-grade dysplasia or villous, including tubulovillous, elements) of the distal colon (left-sided, descending colon and sigmoid or rectum) to 777 gender- and age-matched controls who were screen-negative for left-sided adenoma. Compared to those with homozygous genotypes predicting low EPHX1 activity, advanced adenoma risks tended to be elevated for carriers of (113)TyrTyr [odds ratios (OR), 1.5; 95% confidence intervals (CI), 1.0-2.2] and (139)ArgArg (OR, 1.4; 95% CI, 0.8-2.5) and for subjects who carried a greater number of the alleles ((113)Tyr or (139)Arg) associated with high predicted enzymatic activity (P(trend) = 0.03). The increased risk associated with the increasing number of putative high-activity alleles was most apparent among current and recent (quit <10 years) cigarette smokers (P(trend) = 0.02). In conclusion, EPHX1 variants at codon 113 and 139 associated with high predicted enzymatic activity appear to increase risk for colorectal adenoma, particularly among recent and current smokers.
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PMID:Microsomal epoxide hydrolase polymorphisms and risk for advanced colorectal adenoma. 1566 89

NADP(H):quinone oxidoreductase 1 (NQO1) and microsomal epoxide hydrolase (EPHX1, also mEH) are attractive candidate enzymes for association with colorectal neoplasia because they metabolize a number of compounds including polycyclic aromatic hydrocarbons (PAHs) that have been linked with colorectal carcinogenesis. We examined the relationship between NQO1C609T, mEH3, mEH4 and risk of sporadic distal colorectal adenomas in one of the largest case-control studies of 946 polyp-free controls and 894 cases, all participants of the UK Flexible Sigmoidoscopy Screening (UKFSS) Trial. The polymorphisms were examined as independent risk factors and evidence for interaction with smoking and alcoholic drinks was sought. The NQO1 609*T allele was positively associated with high-risk adenoma in this population [odds ratio (OR), 1.36; 95% confidence interval (CI), 1.02-1.83]. Elevated risk estimates were seen in smokers independently of the genotype but the association was stronger among current smokers with the heterozygous variant genotype (OR, 4.24; 95% CI, 2.54-7.09). It was reported for the first time that the association between alcohol and colorectal adenoma was modified by NQO1C609T genotype, such that the relation between alcohol and colorectal adenoma was stronger among those with the common C/C genotype (OR, 1.49; 95% CI, 1.11-2.02; P-interaction = 0.024). There was no association between mEH3 and mEH4 variants and colorectal adenoma risk and no effect modification by alcohol and smoking. These findings provide evidence for an important role of the NQO1C609T polymorphism in susceptibility of colorectal adenomas. Alcohol increases risk of colorectal adenoma in carriers of the high-activity genotype possibly through enhanced activation of alcohol-related procarcinogens.
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PMID:Role of NQO1C609T and EPHX1 gene polymorphisms in the association of smoking and alcohol with sporadic distal colorectal adenomas: results from the UKFSS Study. 1708 76