Search results for "Microsomal epoxide hydrolase"
showing 10 items of 50 documents
Dependency of the in vitro stabilization of differentiated functions in liver parenchymal cells on the type of cell line used for co-culture.
1992
The differentiation status in cultures of primary rat liver parenchymal cells was determined by measuring the activities of various xenobiotic metabolizing enzymes. Most enzyme activities dropped rather rapidly in monocultures of parenchymal cells. The protein content and the activities of cytosolic epoxide hydrolase, glutathione S-transferase, and alpha-naphthol UDP-glucuronosyl transferase were, however, well stabilized in 7-day-old co-cultures of parenchymal cells with two different lines of rat liver nonparenchymal epithelial cells (NEC1 and NEC2). Phenol sulfotransferase and microsomal epoxide hydrolase activity were reduced in this coculture system after 7 days to about 30 and 20% of …
Interaction of valproic acid and some analogues with microsomal epoxide hydrolase.
1992
Abstract Valproic acid (VPA) and its analogues valpromide (VPM), valproyl-Coenzyme A (VP-CoA) and valproyl-ethylester (VPE) were examined as potential inhibitors of microsomal epoxide hydrolase (mEHb) using styrene-7,8-oxide (STO) and benzo(a)pyrene-4,5-oxide (BPO) as enzyme substrates. The effect of each potential inhibitor was examined using mEHb from rat liver, human livers (from a child, woman and man) and from human placenta. Of the compounds tested, only VPM (2 mM) expressed significant inhibition of mEHb activity with a maximum inhibition of 49%, 48%, 35% and 33% for liver microsomes from the child, woman, man and rat, respectively, using STO (2 mM) as substrate. Human placenta mEHb …
Importance of Individual Enzymes in the Control of Ultimate Carcinogens
1995
The metabolic activation of most chemical mutagens and carcinogens is a prerequisite for their mutagenic and carcinogenic activity. Reactive metabolites are under the control of activating, inactivating and precursor sequestering enzymes. These enzymes are under the long-term control of induction and repression and under the short-term control of posttranslational modification. As far as carcinogen-metabolizing enzymes are concerned, posttranslational modification has received little attention. This short-term regulation may be especially important since it works fast and may affect the enzymatic activity as well as the degradation of the enzyme. The enzymatic activity is modified by activa…
Catalytic triad of microsomal epoxide hydrolase: replacement of Glu404 with Asp leads to a strongly increased turnover rate
1998
Microsomal epoxide hydrolase (mEH) belongs to the superfamily of α/β-hydrolase fold enzymes. A catalytic triad in the active centre of the enzyme hydrolyses the substrate molecules in a two-step reaction via the intermediate formation of an enzyme-substrate ester. Here we show that the mEH catalytic triad is composed of Asp226, Glu404 and His431. Replacing either of these residues with non-functional amino acids results in a complete loss of activity of the enzyme recombinantly expressed in Saccharomyces cerevisiae. For Glu404 and His431 mutants, their structural integrity was demonstrated by their retained ability to form the substrate ester intermediate, indicating that the lack of enzymi…
Endogenous Role of Microsomal Epoxide Hydrolase
2005
The specific activities of microsomal epoxide hydrolase with 16α,17α-epoxyandrosten-3-one (androstene oxide) as substrate were measured in various metabolically important and in various steroidogenic organs of the male and female rat and compared with the activities of 16α,17α-epoxyestratrienol (estroxide) and benzo[a]pyrene 4,5-oxide. Androstene oxide was an exceptionally good substrate. The specific activities differed widely between organs but the ratio of the activities towards these substrates was constant in all organs investigated. The ratios compared to benzo[a]pyrene 4,5-oxide were 2.5 for estroxide, and 8.6 for androstene oxide. The ontogenetic development of specific epoxide hydr…
Stable Expression of Heterologous Microsomal Epoxide Hydrolase in BHK21 Cells: Influence on the Mutagenicity of Benzo[a]pyrene 4,5-Oxide
1992
Most environmental mutagens and carcinogens require metabolic activation to electro- philic intermediates capable of reacting with cellular target structures, such as DNA. These electrophilic intermediates are in addition subject to metabolic detoxification. This metabolism is mainly controlled by enzymes whose expression is very variable. Among other things, various enzymes are inducible by environmental chemicals. Understanding the toxicology of chemicals (for example, species differences, idiosyncrasias, organotropisms) therefore requires knowledge of critical host factors. One approach towards this goal involves the use of purified enzymes in metabolism and toxicological studies (Glatt …
Role of the Well-Known Basic and Recently Discovered Acidic Glutathione S-Transferases in the Control of Genotoxic Metabolites
1991
Glutathione S-transferases (GSTs; E.C. 2. 5. 1. 18) are a family of enzymes which have increasingly attracted the interest of toxicologists, pharmacologists, biochemists and clinicians since their discovery in 1961 (1). Initially, GSTs were believed to serve as intracellular transport proteins for endogenous compounds with limited solubility in water, thus acting as an intracellular equivalent to albumin in blood plasma. In this assumed capacity of reversible binding and transport of various ligands, the corresponding protein was named ligandin (2). Following the discovery of abundant GST occurrence in most forms of aerobic life including plants, and the GST-catalysed conjugation of a wide …
Species Differences in Enzymes Controlling Reactive Epoxides
1987
Activities of enzymes involved in the metabolic formation and catabolism of epoxides were determined in liver subcellular preparations from 11 mammalian species and various strains of mice. The most conspicuous finding was that the activities of the microsomal epoxide hydrolase were clearly lower in the mouse than in the other species. This invited the working hypothesis that epoxides may be involved in mouse liver carcinogenesis. The carcinogens may be metabolised themselves to reactive epoxides or they may modify the metabolism of epoxides formed from endogenous or other foreign compounds. To examine the former point, phenobarbital, DDT (1,1-bis(p- chlorophenyl)-2,2,2-trichloroethane), li…
Epoxide Hydrolase Isoenzymes and their Individual Contribution to the Control of Toxic Metabolites
1991
Epoxides are highly strained three membered cyclic ethers which are formed in vivo by the microsomal cytochrome P450 dependent monooxygenases as intermediates of several important biosynthetic pathways (leukotriene A4, squalene 2, 3-oxide) and as metabolites of numerous xenobiotic compounds containing olefinic or aromatic double bonds. Further transformation of these epoxides may occur by either, rearrangement to phenols, aliphatic aldehydes, or ketones; by cytochrome P450 dependent reduction to the parent compound; or by spontaneous or enzymatic conjugation to gluta-thione. Epoxides may also bind covalently to cellular nucleophiles, such as proteins and nucleic acids thus eliciting carcino…
Focal elevation of liver microsomal epoxide hydrolase in early preneoplastic stages and its behaviour in the further course of hepatocarcinogenesis.
1981
Abstract Treatment of rats with N-nitrosomorpholine (NNM) for 7 weeks led to a focal increase in liver microsomal epoxide hydrolase (EH) as early as 2 weeks after withdrawal of the carcinogen. This treatment also leads to hyperplastic nodules and liver tumors, but much later. At the same early time point, ATPase activity was decreased in the same islands. Most of these areas already had increased γ-glutamyltranspeptidase activity. The increase in EH at this early time point was more distinct than the decrease in ATPase which has thus far been considered a suitable marker of the earliest stages in hepatocarcinogenesis. The focal increase in EH was also observed in all benign hepatomas, but n…