Disease relevance of Ephx1

• Induction of phase 2 detoxication enzymes [e.g., glutathione transferases, epoxide hydrolase, NAD(P)H: quinone reductase, and glucuronosyltransferases] is a powerful strategy for achieving protection against carcinogenesis, mutagenesis, and other forms of toxicity of electrophiles and reactive forms of oxygen [1].
• Quantiation of epoxide hydrolase released from hyperplastic nodule and hepatoma microsomes [2].
• The effects of imidazole antifungal agents, including ketoconazole, clotrimazole, miconazole, and econazole, on the expression and regulation of microsomal epoxide hydrolase (mEH) were examined in rat hepatic tissue (doses of agents, 150 mg/kg of body weight/day, orally) [3].
• Microsomal epoxide hydrolase (mEH), an epoxide detoxifying enzyme and putative cell surface autoantigen, is inducible by xenobiotics and by certain pathophysiological conditions (e.g., tumorigenesis and protein-calorie malnutrition) [4].
• Induction of alkoxyresorufin O-dealkylases, epoxide hydrolase, and liver weight gain: correlation with liver tumor-promoting potential in a series of barbiturates [5].

High impact information on Ephx1

• Antibodies against homogeneous epoxide hydratase provide evidence for a single enzyme hydrating styrene oxide and benz(a)pyrene 4,5-oxide [6].
• Differences between the species in the distribution of the cytosolic and microsomal hydrolases and in their substrate specificities and pH optima demonstrate why epoxide hydrolase activity in the cytosolic fraction was not detected earlier in spie of intensive work on the microsomal epoxide hydrolase [7].
• Aryl hydrocarbon hydroxylase and epoxide hydratase activities: age effects in mammary epithelial cells of Sprague-Dawley rats [8].
• Epoxide hydrolase is a marker for the smooth endoplasmic reticulum in rat liver [9].
• 8-Methylbenz[a]anthracene (8-MeBaA) transdihydrodiol metabolites were isolated by reversed-phase and normal-phase HPLCs from incubations of 8-MeBaA with liver microsomes or a reconstituted system containing purified cytochrome P-448 and epoxide hydrolase [10].

Chemical compound and disease context of Ephx1

• Both sense and antisense strands of PCR-amplified mEH DNA were cloned into an M13mp19 phage vector in order to examine the nucleotide sequences of PCR-amplified mEH DNA derived from the poly(A)+ RNA isolated from thiazole- or pyrazine-treated animals [11].
• Microsomal epoxide hydrolase activity in rat H4-II-E hepatoma cells was refractory to induction, except by trans-stilbene oxide treatment, which caused a 70% increase in benzo[a]pyrene 4,5-oxide hydrolase activity [12].
• Gene induction confirmed involvement of glutathione-S-transferase isozymes and epoxide hydrolase in bromobenzene metabolism and identified many genes possibly relevant in bromobenzene toxicity [13].
• Prevention of c-Jun/activator protein-1 activation and microsomal epoxide hydrolase induction in the rat liver by cysteine during protein-calorie malnutrition [14].
• A previously validated small mammal trauma model, hindlimb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on two of the major hepatic enzymes of detoxification, glutathione S-transferase and epoxide hydrolase [15].

Biological context of Ephx1

• The cDNA and gene for epoxide hydrolase displayed nucleotide sequence identity although they were isolated from different rat strains [16].
• Clones were obtained from a Wistar Furth Charon 35 genomic library by hybridization with a full-length epoxide hydrolase cDNA [16].
• However, a pseudogene for the microsomal xenobiotic epoxide hydrolase was isolated and characterized from the genomic library [16].
• The gene for the xenobiotic epoxide hydrolase is approximately 16 kilobases in length and consists of 9 exons ranging in size from 109 to 420 base pairs and 8 intervening sequences, the largest of which is 3.2 kilobases [16].
• Complementary DNA and amino acid sequence of rat liver microsomal, xenobiotic epoxide hydrolase [17].

Anatomical context of Ephx1

• This level of induction correlates well with the 5-fold induction in catalytic activity of epoxide hydrolase (using styrene 7,8-oxide as substrate) in microsomes isolated from phenobarbital-treated rats [18].
• Therefore, we suggest that chronic phenobarbital administration increases the amount of functional epoxide hydrolase in rat liver microsomes by way of an increase in the translatable mRNA level encoding for the enzyme [18].
• Liver poly(A)+RNA isolated from untreated and phenobarbital-treated rats has been translated in the rabbit reticulocyte cell-fre system in order to determine the level of translationally active epoxide hydrolase (EC 3.3.2.3) mRNA [18].
• 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 [19].
• Hyperplastic nodule and hepatoma cytosol fractions had significant amounts of epoxide hydrolase, but normal liver cytosol fraction had no immunologically detectable hydrolase [2].

Associations of Ephx1 with chemical compounds

• Only a single functional epoxide hydrolase gene was identified and no evidence of hybridization to the genes for the microsomal cholesterol epoxide hydrolase or the cytosolic epoxide hydrolase was observed [16].
• Thus, repeated inhalation exposure to D4 induces CYP enzymes and epoxide hydrolase in a manner similar to that observed for phenobarbital (PB) [20].
• Evaluation of octamethylcyclotetrasiloxane (D4) as an inducer of rat hepatic microsomal cytochrome P450, UDP-glucuronosyltransferase, and epoxide hydrolase: a 28-day inhalation study [20].
• The epoxide hydratase inhibitor 1,2-epoxy-3,3,3-trichloropropane was found to eliminate all dihydrodiol formation and markedly inhibit the formation of several dimethylbenzanthracene metabolites [21].
• Benzo(a)pyrene is metabolically and stereospecifically converted by mixed-function oxidases of rat liver microsomes and epoxide hydratase (glycol hydro-lyase (epoxide-forming), EC 4.2.1.63)to the single enantiomer (-)r-7,t-8-dihydroxy-7,8-dihydrobenzol (A) pyrene [22].

Physical interactions of Ephx1

• Alcohol dehydrogenase-coupled spectrophotometric assay of epoxide hydratase activity [23].

Regulatory relationships of Ephx1

• In contrast to the P-450s, microsomal epoxide hydrolase mRNAs were expressed at relative homogeneous amounts throughout the brain. beta-Naphthoflavone markedly increased the CYP1A1 and CYP1A2 mRNA contents of each brain region investigated, although this agent did not affect levels of epoxide hydrolase [24].
• Three of four regimens increased epoxide hydrolase activity (150-600% of control) and DT-diaphorase activity (150-200% of control) [25].
• Evidence was provided through kinetic studies that the epsilon-Gua adducts are formed primarily from 2-haloxiranes; consistent with this view, epoxide hydrolase inhibited the formation of N2,3-epsilon-Gua from vinyl chloride but alcohol dehydrogenase did not [26].

Other interactions of Ephx1

• Etanercept treatment increased Cyp2c23 expression and lowered epoxide hydrolase expression [27].
• Induction of microsomal epoxide hydrolase by sulfur amino acid deprivation via the pathway of C-Jun N-terminal kinase and its extracellular exposure during cell death [4].
• 3. Administration of 2-acetylaminofluorene resulted in the induction of two polypeptides; evidence is presented that suggests that one of these is a species of epoxide hydratase [cf. Levin, Lu, Thomas, Ryan, Kizer & Griffin (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 3240-3243] ANd that the other may be a novel haemopolypeptide [28].
• Indomethacin in vitro also caused a loss of cytochrome b5, NADH-cytochrome b5 reductase, NADPH-cytochrome c reductase and epoxide hydrolase activities, but an activation of UDP-glucuronyltransferase [29].
• Phenobarbital (PB)-mediated induction of five forms of cytochrome P450 (CYP2B1, CYP2B2, CYP3A1, CYP2A1, and CYP2C6) and epoxide hydrolase is highly suppressed, at the transcriptional level, in Wistar Furth (WF) relative to Fischer 344 (F344) female rats [30].

Analytical, diagnostic and therapeutic context of Ephx1

• Also, Southern blot analysis of restricted liver DNA from inbred Fischer 344 and Wistar Furth rat strains, and outbred Sprague-Dawley rats indicated a high degree of structural similarity for the epoxide hydrolase gene within these three strains [16].
• Using high pressure liquid chromatography we have now studied the benzo(a)pyrene metabolites formed by rough and smooth endoplasmic reticulum, nuclei, and plasma membrane as well as mitochondrial fractions and investigated the metabolic cooperation between the monooxygenases and epoxide hydrolase in these fractions [31].
• Epoxide hydrolase, another microsomal enzyme involved in the metabolism of xenobiotics, was also quantitated by radial immunodiffusion after prior treatment of rats with microsomal enzyme inducers [32].
• The kinetics of oval cell proliferation in the liver and their fate were studied by combined autoradiography and immunohistochemical staining for epidermal prekeratin and epoxide hydrolase (EH) [33].
• Clotrimazole, however, maintained the activated mEH transcription rate at 24 hr after treatment, exhibiting a 11-fold increase, compared with control [3].

References