Human Hepatic Microsomal Epoxide Hydrolase: Comparative Analysis of Polymorphic Expression

Hassett, Christopher; Lin, Jing; Carty, Cara L.; Laurenzana, Elizabeth M.; Omiecinski, Curtis J.

doi:10.1006/abbi.1996.9794

Cited by 119 publications

(77 citation statements)

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“…The present study has examined genotype and not phenotype. There is clear evidence that the presence of a 'slow' exon 3 allele does confer lower enzyme activity, but genotype alone is insufficient to explain the variation of microsomal epoxide hydrolase enzyme activity seen in population studies (Hassett et al, 1997). In particular, the effect of carrying both exon 3 and exon 4 polymorphisms is undetermined and, thus, assumptions concerning enzyme activity from our study should be necessarily guarded.…”

Section: Discussionmentioning

confidence: 74%

Microsomal epoxide hydrolase gene polymorphism and susceptibility to colon cancer

et al. 1998

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The colon is subject to oxidative and free radical damage by both products of endogenous metabolism and bacterial fermentation within the gut lumen. These injurious stimuli may cause cell damage or cell death or even lead to mutations, resulting in tumour initiation and progression. Colon cancer is a common disease, with the highest incidence in developed countries. The aetiology is unknown, but in addition to diet and cigarette smoking (Giovannucci and Willett, 1994) there is a complex polygenic background that determines individual susceptibility to disease. There is currently much interest in the roles of oncogenes, tumoursuppressor genes and mismatch repair enzymes in colon cancer (Tomlinson et al, 1997). In addition, interindividual variation in the ability to dispose of reactive xenobiotics catalysed by glutathione S-transferases GST-M1 and GST-T1 has been investigated (Lang et al, 1986;Strange et al, 1991;Zhong et al, 1993;Chenevix-Trench et al, 1995). However, results from a number of studies show only weak and inconsistent associations with disease susceptibility. N-acetyltransferase 2 (NAT-2) polymorphism may be implicated in susceptibility to colon cancer (Lang et al, 1986;Wohlleb et al, 1990;Illett et al, 1994;Probst-Hensch et al, 1995), but there is evidence that its relationship may be by linkage with other genes rather than causally (Hubbard et al, 1997).We have used a polymerase chain reaction (PCR) strategy to investigate whether polymorphisms in the microsomal epoxide hydrolase gene (mEPHX) (Hassett et al, 1994) have any relationship to colon cancer. The enzyme is expressed in many tissues, including colon and liver. Polymorphisms of mEPHX may have functional significance. There is variation in exon 3, where a T to C alteration changes tyrosine residue 113 to histidine and is associated with lower enzyme activity when expressed in vitro. By contrast, A to G transition in exon 4 changes histidine residue 139 to arginine and produces increased enzyme activity. The effect of combining the alleles has not been established. The activity of mEPHX varies more than 50-fold in Caucasians (Omiecinski et al, 1993). This variation of activity is, thus, due to a combination of genetic polymorphism, transcriptional and post-transcriptional control of gene expression. MATERIALS AND METHODS Controls and cancer casesControl blood samples (n = 203) were obtained anonymously from the Scottish National Blood Transfusion Service. These were Caucasian individuals aged between 18 and 65 years with equal sex distribution. This group has been previously described (Cantlay et al, 1994) and was drawn from the same geographical area as the cancer study group. The presence of colorectal neoplasia was not specifically excluded, but all patients were healthy. Peripheral blood from patients with colorectal cancer was collected from a consecutive series of operable colorectal cancer cases after surgery in four local hospitals between 1988 and 1993 (n = 101). Cancer patient dataCancer diagnosis was confirmed histopathologically...

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Section: Discussionmentioning

confidence: 74%

Microsomal epoxide hydrolase gene polymorphism and susceptibility to colon cancer

et al. 1998

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“…However, when results were normalized to mEH immunodetectable protein levels, the variants appeared to encode only marginal phenotypic differences. These data, together with results from additional studies [89,90], suggest that differences in protein stability among the variant mEH proteins may factor into the basis of observed interindividual differences in mEH phenotype. Additionally, seven other 5%-flanking region genetic polymorphisms have been described [91], and may also impact mEH gene transcriptional activity and resulting cellular phenotype.…”

Section: Introductionmentioning

confidence: 78%

Epoxide hydrolases: biochemistry and molecular biology

Fretland

Omiecinski

2000

Chemico-Biological Interactions

273

185

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Epoxides are organic three-membered oxygen compounds that arise from oxidative metabolism of endogenous, as well as xenobiotic compounds via chemical and enzymatic oxidation processes, including the cytochrome P450 monooxygenase system. The resultant epoxides are typically unstable in aqueous environments and chemically reactive. Biol. Chem. 260 (1985) 1630-1640). Therefore, it is of vital importance for the biological organism to regulate levels of these reactive species. The epoxide hydrolases (E.C. 3.3.2.3) belong to a sub-category of a broad group of hydrolytic enzymes that include esterases, proteases, dehalogenases, and lipases Beetham et al. (DNA Cell Biol. 14 (1995) 61 -71). In particular, the epoxide hydrolases are a class of proteins that catalyze the hydration of chemically reactive epoxides to their corresponding dihydrodiol products. Simple epoxides are hydrated to their corresponding vicinal dihydrodiols, and arene oxides to trans-dihydrodiols. In general, this hydration leads to more stable and less reactive intermediates, however exceptions do exist. In mammalian species, there are at least five epoxide hydrolase forms, microsomal cholesterol 5,6-oxide hydrolase, hepoxilin A 3 hydrolase, leukotriene A 4 hydrolase, soluble, and microsomal epoxide hydrolase. Each of these enzymes is distinct chemically and immunologically. Table 1 illustrates some general properties for each of these classes of hydrolases. Fig. 1 provides an overview of selected model substrates for each class of epoxide hydrolase.

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“…mEH activity ex vivo exhibits a relatively large interindividual variation, [16][17][18][19] which might be explained, at least in part, by differences in mEH gene sequences. Genotype/ phenotype correlations, however, are imperfect, indicating an effect of induction/inhibition of enzyme expression possibly because of posttranscriptional/posttranslational mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…15 Microsomal epoxide hydrolase (mEH) is expressed in all tissues, with the highest levels in liver, kidney, and testis, 13,16 and it is primarily involved in the metabolism of xenobiotics with a wide substrate specificity. There is evidence for polymorphic mEH expression in humans, [16][17][18][19] and allelic variants of mEH have been identified. 20,21 Two point mutations in the coding sequence lead to amino acid changes, Tyr113His and His139Arg, which affect mEH activity by influencing protein stability.…”

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confidence: 99%

Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease

Sonzogni

Silvestri

et al. 2002

Hepatology

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Factors influencing the progression of liver disease and the development of hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) infection are poorly understood. Inherited variations of drug-metabolizing enzyme (DME) activities may affect liver damage and cancer risk by modifying individual susceptibility to endogenous or exogenous toxic compounds. We investigated the association of liver disease severity with common alleles of microsomal epoxide hydrolase (mEH), an enzyme involved in the metabolism of highly reactive epoxide intermediates. Three polymorphisms (Tyr113His, His139Arg, and ؊613C/T) were analyzed by polymerase chain reaction (PCR) restriction fragment length polymorphisms (RFLPs) in 394 patients at different stages of disease, including 92 asymptomatic carriers, 109 patients with chronic hepatitis, 100 patients with cirrhosis, and 93 patients with HCC. Reference allele frequencies were obtained from 99 healthy blood donors. Allele distributions between categories were compared using the 2 test; odds ratios (ORs) and 95% CI were calculated to express relative risks. Allele frequencies among 99 healthy controls were as follows: 15.1% for 113His/His, 4.0% for 139Arg/Arg, and 46.5% for ؊613C/T. mEH 113His/His homozygotes were overrepresented in advanced stages of disease, in particular among HCC patients (27.9%; P ‫؍‬ .03; OR, 2.2; 95% CI, 1.0-4.6). Differences were more pronounced among men and between extreme patient categories. When mEH genotypes were combined to express a metabolic phenotype, very slow metabolizers were highly prevalent among cirrhotic and HCC patients (18% vs. 3.3% in carriers; P < .001). In conclusion, mEH gene polymorphisms were significantly associated with HCV-related liver disease severity and HCC risk. Men were at higher risk than women; this might be explained by hormonal regulation of gene expression or by differential exposure to environmental toxins. (HEPATOLOGY 2002;36:195-201.) T he worldwide burden of deaths caused by liver diseases and liver cancer, which usually arises in the setting of cirrhosis and chronic viral hepatitis, is estimated to be approximately 1.3 million/yr. 1 Chronic hepatitis C virus (HCV) infections account for over 80% of cases of cirrhosis and hepatocellular carcinomas (HCC) in Italy, 2 for which over 2 million anti-HCV-positive cases are estimated. 3 HCV-related liver disease displays a multiplex phenotype in which environmental and viral factors are likely to act in concert with individual susceptibility to induce liver damage. Overall penetration of disease expression is low, because less than 20% of infected individuals will develop cirrhosis over a 20-to 30-year period. 4 Determinants of HCV pathogenesis are barely known and include age at infection, 5 disease duration, 4 sex, 6 modes of transmission, 7 immunogenetic variables, 8 and viral heterogeneity, 9 but these factors account for only a small part of the clinical variability of the disease. Dietary factors, inherited metabolic defects, such as hemochromatosis, 10 and alc...

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Human Hepatic Microsomal Epoxide Hydrolase: Comparative Analysis of Polymorphic Expression

Cited by 119 publications

References 0 publications

Microsomal epoxide hydrolase gene polymorphism and susceptibility to colon cancer

Microsomal epoxide hydrolase gene polymorphism and susceptibility to colon cancer

Epoxide hydrolases: biochemistry and molecular biology

Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease

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