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Results for “Epoxide Hydrolases”

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At least 19 recordsLinked to original sources
PubMed1979

Immunocytochemical localization of epoxide hydrase in hyperplastic nodules induced in rat liver by 2-acetylaminofluorene.

A knowledge of the biological characteristics of carcinogen-induced hyperplastic nodules of rat liver may be important in the understanding of cancer development. Although its biological role remains to be elucidated, the level of microsomal epoxide hydrase (epoxide hydrolase, EC 3.3.2.3) is 5- to 7-fold greater in hyperplastic nodules nodules induced by feeding the hepatocarcinogen 2-acetylaminofluorene than in liver of control rats. After removal of the carcinogen from the diet, the high level of the enzyme is maintained in those nodules that persist and in the hepatocellular carcinomas that subsequently develop. The availability of antibody to the epoxide hydrase made it possible to use electron microscopic immunocytochemistry to localize this enzyme in the cells of hyperplastic nodules. The immunocytochemical procedure provides direct visual evidence for the presence of this enzyme in smooth endoplasmic reticulum and also in rough endoplasmic reticulum (including the nuclear envelope) of the nodule's parenchymal cells.

2-Acetylaminofluorene↗
PubMed2026

Molecular mechanisms of neuroendocrine regulation of molting in the Chinese mitten crab (Eriocheir sinensis): A transcriptomic analysis based on eyestalk ablation model.

Molting disability severely restricts the sustainable aquaculture of the Chinese mitten crab, yet the neuroendocrine mechanisms coordinating physiological responses remain poorly understood. Using unilateral eyestalk ablation to remove the primary source of molt-inhibiting hormone (MIH), we performed time-resolved transcriptomic profiling of the thoracic ganglion at 24 h (early premolt) and 48 h (ecdysis) post-ablation. We identified 2825 differentially expressed genes and uncovered a biphasic molecular response. At 24 h, the thoracic ganglion activates pathways associated with neuromuscular adaptation, oxidative stress, and cardiac muscle contraction. Notably, the arachidonic acid metabolism pathway is selectively rewired: cytochrome P450 ω-hydroxylases (CYP2J2, CYP4V2) are upregulated, while competing branches (epoxide hydrolase, cyclooxygenase) are suppressed, promoting local synthesis of the potent vasoconstrictor 20-HETE within the thoracic ganglion. This enzymatic switch provides a mechanistic link between MIH withdrawal and the local generation of elevated hemolymph pressure required for molting. By 48 h, the transcriptional program shifts toward chitin-based extracellular matrix remodeling, glycosphingolipid biosynthesis, and synaptic reorganization. Collectively, our findings redefine the thoracic ganglion as an active neuroendocrine integrator that translates reduced MIH signaling into phased physiological outputs, revealing a "neuro-endocrine-hemolymph pressure" regulatory axis. This study provides novel molecular targets (e.g., CYP2J2, CHS1, UGCG) for mitigating molting disability in E. sinensis aquaculture.

Animals↗
PubMed2025

Sex-dependent upregulation in oxylipins involved in inflammation resolution in the cerebellum of Niemann-Pick disease C1 mice.

Unresolved inflammation in the cerebellum is implicated in motor and cognitive decline in Niemann-Pick disease type C (NPC), a neurodegenerative lysosomal storage disorder caused by pathogenic mutations in the Npc1 gene encoding a cholesterol transporter protein. It is unclear whether unresolved inflammation in NPC stems from impairments in lipid-mediated resolution. For this reason, free lipid mediators (i.e., oxylipins) involved in inflammation resolution, as well as esterified lipid mediators known to regulate the bioavailability of free oxylipins were quantified using Reverse-Phase Ultra- Performance Liquid Chromatography coupled to negative Electrospray Ionization and Triple Quadrupole Tandem Mass Spectrometry (RP-UPLC-ESI(-)-QqQ-MS/MS) in Npc1 knock-in (NPC1ki) and Wildtype (WT) mice. Total cholesterol and fatty acids including polyunsaturated fatty acid (PUFA) precursors to oxylipins, were quantified using Gas Chromatography coupled to Flame Ionization Detection (GC-FID). Compared to WT mice, female NPC1ki mice, but not males, exhibited significantly elevated levels of free pro-resolving fatty acid epoxides (EpETrE and EpDPE) from the cytochrome P450 (CYP) pathway. Esterified mono- and dihydroxy lipid mediators derived from the lipoxygenase (LOX) and soluble epoxide hydrolase (sEH) pathways were mainly increased in NPC1ki females, suggesting enhanced sequestration of pro-inflammatory LOX and sEH metabolites. While PUFAs and cholesterol concentrations were not significantly different between groups, myristic (C14:0) and palmitoleic acid (C16:1n-7) were significantly elevated in female NPC1ki mice compared to WT controls. These findings suggest sex-specific adaptations in inflammation resolution pathways in NPC, with females exhibiting distinct inflammatory responses that may drive sex-related differences in disease pathogenesis. Our findings underscore the need for sex-specific therapeutic approaches to improve NPC treatment outcomes.

Animals↗
PubMed2026

Host eicosanoid signals define a granuloma fibroblast population that coordinates mycobacterial containment.

Genetic variation at the leukotriene A4 hydrolase (LTA4H) locus is associated with tuberculosis (TB) severity and outcome. Here, we define a unique population of peripheral fibroblasts at the mycobacterial granuloma, the central immune structure in TB, whose recruitment and functions are coordinated by lta4h-dependent signals. Using single-cell profiling of zebrafish mycobacterial infections, we identify a layer of lta4h-dependent recruited fibroblasts at the granuloma's edge with mesenchymal and stem-like expression signatures, including aldh1a3 expression. Ablation of these cells compromises bacterial containment at the structure's periphery. Similarly, genetic disruption of apolipoprotein D, produced specifically in granuloma-associated fibroblasts, results in an altered eicosanoid balance, decreased inflammation, and increased dissemination of infection. In humans, this granuloma-associated fibroblast population is distinct from myofibroblasts, interacts with LTA4H-expressing macrophages, and is prominent across diverse TB granuloma types. These results link a host genetic susceptibility locus to the recruitment and function of a specialized fibroblast population that limits bacterial dissemination.

Animals↗
PubMed1977

Hydration of arene and alkene oxides by epoxide hydrase in human liver microsomes.

The comparative hydration of styrene 7,8-oxide, octene 1,2-oxide, naphthalene 1,2-oxide, phenanthrene 9,10-oxide, benzo[a]anthracene 5,6-oxide, 3-methylcholanthrene 11,12-oxide, dibenzo[a,h]anthracene 5,6-oxide, and benzo[a, 7,8-, 9,10-, and 11,12-oxides to their respective dihydrodiols was investigated in microsomes from nine human autopsy livers. The substrate specificity of the epoxide hydrase in human liver microsomes was very similar to that of the epoxide hydrase in rat liver microsomes. Phenanthrene 9,10-oxide was the best substrate for the human and rat epoxide hydrases and dibenzo[a,h]anthracene 5,6-oxide and benzo[a-a)pyrene 11, 12-oxide were the poorest substrates. Plotting epoxide hydrase activity obtained with one substrate against epoxide hydrase activity for another substrate for each of the nine human livers revealed excellent correlations for all combinations of the 11 substrates studied (r = 0.87 to 0.99). The data suggest the presence in human liver of a single epoxide hydrase with broad substrate specificity. However, the results do not exclude the possible presence in human liver of several epoxide hydrases that are under similar regulatory control. These results suggest the need for further investigation to determine whether there is a safe epoxide of a drug whose in vivo metabolism is predictive of the capacity of different individuals to metabolize a wide variety of epoxides of drugs and environmental chemicals.

Alkenes↗
PubMed1976

Prevention of benzo(a)pyrene-induced mutagenicity by homogeneous epoxide hydratase.

Benzo(a)pyrene and benz(a) anthrancene which, in contrast to the K-region epoxides benzo(a)pyrene 4,5-oxide and benz(a)anthracene 5,6-oxide, are not mutagenic to Salmonella typhimurium TA 1537 in the absence of mammalian enzyme preparations, were activated by liver microsomes from C3H mice, which had not received any pretreatment, to mutagens reverting this tester strain to histidine prototrophy. Addition of epoxide hydratase inhibitors greatly increased this mutagenicity and addition of pure epoxide hydratase reduced it by more than 95% down to the range of spontaneous mutations as observed in absence of any added mutagen. This demonstrates than the metabolic pathway responsible for the mutagenicity of both polycyclic hydrocarbons observed in this system proceeds entirely via an epoxidation pathway and that the responsible metabolites are epoxides or species arising from them. Moreover, further metabolism by epoxide hydratase does not lead to produce contributing to the mutagenicity observed with the tester strain used. Finally, the epoxides relevant for the observed mutagenicity are substrates for epoxide hydratase; indeed, modest amounts of the pure enzyme can prevent the mutagenic effect.

Benz(a)Anthracenes↗
PubMed1978

Stimulatory effect of cigarette smoke on the metabolism and covalent binding of benzo(a)pyrene in the trachea of the rat.

The activity of aryl hydrocarbon hydroxylase (substrate: benzo(a)pyrene) was increased in the tracheas of rats exposed to cigarette smoke for 1 h daily for either 1 or 10 days. However the degree of increase in activity was lower in the trachea than in the lung. After a single exposure, activity in the trachea was at its highest level 12 h following exposure (3.2-fold compared to the control), but had returned to the control level within 24 h. Also, the amounts of covalently bound metabolites of benzo(a)pyrene were increased (2-fold) in nucleic acid and protein fractions of the trachea, when the rats were killed 12 h after a single cirgarette smoke exposure. No significant changes in activity of epoxide hydratase (substrate: styrene oxide) could be detected in the trachea. After repeated exposures the activity of UDP-glucuronosyltransferase (substrate: methylumbelliferone) was increased (1.7-fold) in the trachea.

Animals↗
PubMed1975

Partial purification and separation of multiple forms of cytochrome. P-450 and cytochrome P-448 from rat liver microsomes.

1. Partial purification of liver microsomal cytochrome p-450 results in the separation of two forms of cytochrome p-450 from phenobarbital-treated rats and two forms of cytochrome p-44, from 3-methylcholanthrene-treated rats. 2. Each of the four cytochrome fractions had different spectral properties (absolute spectra, CO differences spectra, and ethylisocyanide difference spectra). 3. The hemeprotein in fractions which elute from a DEAE-cellulose column at 100 mKM KCl fraction IV B) are more highly purified than the hemeproteins (fraction IV A) that elute in the column volume. 4. The more highly purified cytochrome fractions (IV B) contain 9-11 moles of cytochrome P-450 or P-448 per mg protein (an approximately 5-7 fold purification over microsomes) and are enzymatically active in the metabolism of a variety of substrates when combined with lipid and NADPH-cytochrome c reductase. These hemeprotein fractions are free of cytochrome b5 and NADPH-cytochrome c reductase, and the hemeproteins are purified approximately 100-fold with respect to phospholipid. The cytochrome P-450 and P-448 are virtually free of epoxide hydrase.

Animals↗
PubMed1978

A very sensitive gas chromatographic method for the evaluation of styrene oxidase and styrene oxide hydratase activities.

Styrene is a compound widely used in the manufacture of polystyrenic plastics and it has recently been shown to exert mutagenic effects after metabolic activation into styrene oxide by the microsomal mixed function oxidases; this oxide is further converted into inactive styrene glycol. In order to investigate the relative importance of activation and desactivation processes of styrene, we developed a gas chromatographic method which enables us to simultaneously measure styrene oxide and styrene glycol formed after incubation of styrene with microsomal preparations from different tissues. After selective extraction of the two compounds from the incubation mixture, they are derivatized with pentafluorobenzoyl chloride and measured by gas chromatography using an electron capture detector. The high sensitivity of the method, which allows 0.01 ng of both compounds to be measured, as well as its selectiveity, has permitted us to adequately evaluate the kinetic parameters of styrene oxidase and styrene oxide hydratase activities, as well as their modifications under the influence of various pretreatments of the animals.

Animals↗
PubMed1979

Organ specificity of induction of activating and inactivating enzymes by cigarette smoke and cigarette smoke condensate.

Inhalation of cigarette smoke specifically induces the rat lung and kidney aryl hydrocarbon hydroxylase (AHH) in less than 4 h. The epoxide hydratase (EH) and the glutathione S-transferase are not significantly modified by a similar treatment in any of the rat tissues. Compared to the kidney AHH, the lung hydroxylase is 3--4 times more sensitive to small concentrations of cigarette smoke and seems to have a longer biological half-life. In both tissues, the induced AHH presents the same in vitro sensitivity to various inhibitors as a polycyclic hydrocarbon induced AHH. In primary fetal rat liver cell culture, the cigarette smoke condensate fractions (CSCF) induce both the AHH and EH activity. Nevertheless, the AHH activity responds faster and to lower concentrations of CSCF than the EH activity. The liver cell culture constitutes a unique tool for a comparative study of the AHH and EH induction mechanism. Low concentration (10 muM) of benz(a)anthracene induces only the AHH activity while trans-stilbene oxide enhances selectively the EH activity. Appropriate concentrations of CSCF or of phenobarbital (PB) determine a parallel induction of both enzymes. The results are discussed on the basis of (a) the existence of specific mechanisms of AHH regulation in the lung and in the kidney and (b) the existence of coordinated or independent biochemical control of the AHH and EH activity.

Animals↗
PubMed1975

Epoxide hydrase activity in mouse skin eidermis.

By fractionation of mouse epidermis a "microsomal" fraction may be obtained with a specific EH-activity at least 6-7 times higher than that of epidermis homogenates. Such enrichment allows to utilize the radioassay with 7--3H-styrene oxide as substrate which normally is too insensitive for organs with low levels of EH-activities. By the procedure developed the unambiguous demonstration of EH-activity in the epidermis of mouse skin is possible.

Animals↗
PubMed1977

Species differences in activating and inactivating enzymes related to the control of mutagenic metabolites.

Microsomal monooxygenases catalyze the biosynthesis of epoxides from olefinic and aromatic compounds whilst microsomal epoxide hydratase and cytoplasmic glutathione S-transferases are responsible for their further biotransformation. Although catalytically very efficient the cytoplasmic glutathione S-transferases play, due to their subcellular localization, a minor role in the inactivation of epoxides derived from large lipophilic compounds and were, therefore, not included in this study. It was shown with such a lipophilic compound, benzo(a)pyrene, as a model substance and with liver enzyme mediated bacterial mutagenesis as biological endpoint that species and strain differences in epoxide hydratase and monooxygenases are reflected in very dramatic differences in mutagenicity of benzo(a)pyrene which varied from extremely potent to a degree which could easily be overlooked. In order to investigate whether the differences in enzyme activities were causally linked to the observed differences in mutagenicity, the enzyme activities were modulated by inhibition and induction. These manipulations were always accompanied by the corresponding changes in mutagenicity. It is concluded that species such as mice which possess high monooxygenase activity but very low epoxide hydratase activity are much more susceptible than man to those toxic effects which are mediated by metabolically formed epoxides which are substrates of epoxide hydratase. In this regard, it is especially noteworthy that mice possess a much lower hepatic epoxide hydratase activity than man.

Animals↗
PubMed1979

Effect of vitamin A deficiency on rat hepatic and colon epoxide hydrase.

Rat liver microsomes and homogenized mucosal linings prepared from vitamin A-supplemented and deficient male rats were used in metabolic studies of 7-3H-styrene oxide. The colon tissue in deficient animals exhibits a significantly higher value of Vmax than the same tissue from vitamin-supplemented animals. The implications of this finding in addition to our earlier observation 10 is discussed in relation to colon carcinoma.

Animals↗