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

Mertes, I.; Fleischmann, R.; Glatt, Hansruedi; Oesch, Franz

doi:10.1093/carcin/6.2.219

Cited by 55 publications

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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%

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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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Section: Discussionmentioning

confidence: 99%

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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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“…Tissues have developed the capacity to metabolize xenobiotic epoxides through several pathways. Prominent among these is the microsomal epoxide hydrolase (EPHX) 1 pathway.A wide variation of interindividual EPHX1 activities have been reported across human tissues (Mertes et al, 1985;Omiecinski et al, 1993;Hassett et al, 1997). We previously characterized two structural polymorphisms, an exon 3 polymorphism corresponding to amino acid position 113, with a resulting Tyr to His substitution (rs1051740), and an exon 4 polymorphism at position 139, coding for a His-to-Arg sub- …”

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confidence: 99%

The Expression of Human Microsomal Epoxide Hydrolase Is Predominantly Driven by a Genetically Polymorphic Far Upstream Promoter

Yang

Liang

Weyant

et al. 2009

J Pharmacol Exp Ther

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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(ϩ/ϩ) 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.Although xenobiotic metabolism often results in detoxication, in certain instances, both in cases of pharmaceutical and environmental chemical metabolism, bioactivated and highly toxic intermediates are generated. In particular, cellular levels of epoxide moieties resulting from chemical metabolism appear to be critical initiators of toxic damage, including genetic mutation. Frequently reactive and unstable, epoxide metabolites, formed via the action of the cytochrome P450 monooxygenases, have been identified as ultimate carcinogenic and cytotoxic reaction products (Sayer et al., 1985;Thakker et al., 1986;Fretland and Omiecinski, 2000). Ultimately, the overall balance between bioactivation and detoxication pathways will determine the kinetics and fate of reactive intermediates within target cells. It seems likely that interindividual differences in susceptibility to toxic sequelae, including cancer incidence, may be associated with an altered genetic predisposition to detoxify epoxides. Tissues have developed the capacity to metabolize xenobiotic epoxides through several pathways. Prominent among these is ...

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“…A previous study found high interindividual variation in hsEH activity [e.g., more than 500-fold in liver (Mertes et al, 1985)], suggesting the existence of variation in coding or regulatory sequences of the gene. In addition, a study of human twins revealed a genetic component in hsEH enzymatic activity variation (Norris et al, 1989).…”

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Polymorphisms in Human Soluble Epoxide Hydrolase

Srivastava²,

et al. 2003

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Human soluble epoxide hydrolase (hsEH) metabolizes a variety of epoxides to the corresponding vicinal diols. Arachidonic and linoleic acid epoxides are thought to be endogenous substrates for hsEH. Enzyme activity in humans shows high interindividual variation (e.g., 500-fold in liver) suggesting the existence of regulatory and/or structural gene polymorphisms. We resequenced each of the 19 exons of the hsEH gene (EPHX2) from 72 persons representing black, Asian, and white populations. A variety of polymorphisms was found, six of which result in amino acid substitutions. Amino acid variants were localized on the crystal structure of the mouse sEH, resulting in the prediction that at least two of these (Arg287Gln and Arg103Cys) might significantly affect enzyme function. The six variants of the hsEH cDNA corresponding to each single polymorphism and one corresponding to a double polymorphism were then constructed by site-directed mutagenesis and expressed in insect cells. As predicted, Arg287Gln and the double mutant Arg287Gln/Arg103Cys showed decreased enzyme activity using trans-stilbene oxide, trans-diphenylpropene oxide, and 14,15-epoxyeicosatrienoic acid as substrates. Lys55Arg and Cys154Tyr mutants had elevated activity for all three substrates. Detailed kinetic studies revealed that the double mutant Arg287Gln/Arg103Cys showed significant differences in K m and V max . In addition, stability studies showed that the double mutant was less stable than wild-type protein when incubated at 37°C. These results suggest that at least six hsEH variants exist in the human population and that at least four of these may influence hsEH-mediated metabolism of exogenous and endogenous epoxide substrates in vivo.Epoxide hydrolases (EC 3.3.2.3) metabolize exogenous and endogenous epoxides by hydrolyzing them to vicinal diols, which are usually less reactive and less mutagenic because of their higher hydrophilicity. sEH is one of five epoxide hydrolases (the others are hepoxilin EH, leukotriene A 4 hydrolase, cholesterol EH, and microsomal EH), which differ in molecular weight, subcellular localization, pI and substrate specificity.Previous work suggests the existence of one hsEH gene localized to chromosomal region 8p21-p12 (Larsson et al., 1995). The human sEH gene (EPHX2) consists of 19 exons encoding 555 amino acids (Sandberg and Meijer, 1996). Because the human and mouse proteins are 73% identical (Beetham et al., 1995) with 100% identity in residues forming the catalytic triad, the crystal structure of murine sEH (Argiriadi et al., 1999) is a good model for predicting structurefunction correlations of the hsEH. Each monomer of the homodimeric mouse sEH has two domains: an N-terminal domain and a C-terminal catalytic domain connected by a proline rich linker (Argiriadi et al., 1999). The catalytic mechanism involves formation of a covalent alkylenzyme ester intermediate as a result of nucleophilic attack by Asp333. This is subsequently hydrolyzed with assistance of the general base His523 in a charge relay with...

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

Cited by 55 publications

References 0 publications

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

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

The Expression of Human Microsomal Epoxide Hydrolase Is Predominantly Driven by a Genetically Polymorphic Far Upstream Promoter

Polymorphisms in Human Soluble Epoxide Hydrolase

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