Search results for "epoxide"
showing 10 items of 251 documents
Biphenyl and fluorinated derivatives: liver enzyme-mediated mutagenicity detected in Salmonella typhimurium and Chinese hamster V79 cells.
1992
Abstract Hepatocarcinogenic polychlorinated and polybrominated biphenyls usually show negative results in in vitro mutagenicity assays. Problems in their testing result from their low water solubility and their slow rate of metabolism. We therefore investigated better soluble model compounds, namely biphenyl and its 3 possible monofiuorinated derivatives. In the direct test, these compounds proved tobe nonmutagenic in Salmonella typhimurium TA98 and TA100 (reversion to histidine prototrophy) and in Chinese hamster V79 cells (acquisition of resistance to 6-thioguanine). However, when the exposure was carried out in the presence of NADPH-fortified postmitochondrial fraction of liver homogenat…
Metabolic epoxidation of trans-4-acetylaminostilbene: A protective mechanism against its activation to a mutagen
1976
Abstract Trans -4-acetylaminostilbene is activated by liver preparations to mutagens for Salmonella typhimurium . Since this compound is metabolized to the trans -α,β-epoxide and since many epoxides are ultimate mutagens, this epoxide was tested for direct mutagenicity. It was, however, found to be non-mutagenic, and, in contrast to the parent compound, the epoxide was no longer activated by liver preparations to mutagens. The same was found for the β-ketone and for the threo -α,β-dihydrodiol, which are formed metabolically from trans -4-acetylaminostilbene and from its α,β-epoxide. 4-Acetylaminobibenzyl showed a very weak mutagenic activity in the presence of the liver preparation. Thus, i…
The effect of dietary imbalances on the activation of benzo[a]pyrene by the metabolizing enzymes from rat liver.
1987
Abstract Male Sprague-Dawley rats (70–80 g) were fed ad libitum a standard control diet (22% casein, 5% lard), or a high lipid diet (30% lard) or a low protein diet (6% casein) or a standard diet containing 50 ppm phenoclor DP6. After 6 weeks on these diets, the cytochrome P-450 microsomal content, the benzo[ a ]pyrene monooxygenase (BaP-MO) and the epoxide hydrolase (EH) were assayed. The formation of mutagenic B(a)P metabolites which covalently bind with DNA was compared. The activity of BaP-MO and of EH were increased by the high lipid diet (+27% and 106% respectively) and by the phenoclor DP6 treatment (+63% and 400% respectively), compared to the standard diet. In animals fed a low pro…
An impaired peroxisomal targeting sequence leading to an unusual bicompartmental distribution of cytosolic epoxide hydrolase
1991
AbstractTo gain an understanding of the mechanism by which the subcellular distribution of cytosolic epoxide hydrolase (cEH) is directed, we have analyzed the carboxy terminal region of rat liver cEH by means of cDNA cloning to define the structure of its possible peroxisomal targeting sequence (PTS). Purified cEH was subjected to peptide analysis following endoproteinase Glu-C digestion and HPLC-separation of the fragments. The obtained sequence information was used to perform PCR experiments resulting in the isolation of a 680 bp cDNA clone encoding the carboxy terminus of cEH. The deduced amino acid sequence displays a terminal tripeptide Ser-Lys-Ile which is highly homologous to the PTS…
Vitamin K epoxide reductase activity in the metabolism of epoxides
1985
Abstract The importance of vitamine K epoxide reductase for the metabolism of a range of structurally diverse epoxides has been investigated. Vitamin K 1 epoxide is reduced by rat liver microsomes at a rate of 0.47 nmoles/g liver/min. The rate of menadione oxide reduction is not significantly higher than the non-enzymatic reduction rate. No measurable reduction of benzo[ a ]pyrene 4,5-oxide, benzo[ a ]pyrene 7,8-oxide, phenanthrene 9,10-oxide, styrene 7,8-oxide, and dieldrin has been detected, nor could trichothecene T-2 toxin inhibit reduction of vitamin K 1 epoxide. Thus, vitamin K epoxide reductase is very specific for vitamin K 1 epoxide. Taking into account the range of structurally di…
Bisdihydrodiols, rather than dihydrodiol oxides, are the principal microsomal metabolites of tumorigenic trans-3,4-dihydroxy-3,4-dihydrodibenz[a,h]an…
1994
Several studies on metabolism and biological activity of tumorigenic dibenz[a,h]anthracene (DBA) and its derivatives have led to the conclusion that the M-region dihydrodiol, trans-3,4-dihydroxy-3,4-dihydro-DBA (DBA-3,4-dihydrodiol), is the precursor of the ultimate mutagenic and tumorigenic metabolite of DBA with the presumed structure of a bay-region dihydrodiol oxide. Incubations of DBA-3,4-dihydrodiol (50 microM) with the microsomal hepatic fraction of Sprague-Dawley rats pretreated with Aroclor 1254 yielded more than 13 metabolites upon separation by HPLC. anti-3,4-Dihydroxy-1,2-epoxy-1,2,3,4-tetrahydro-DBA [0.27 nmol/(nmol of P450.15 min)] could be identified for the first time by UV …
The 3,4-oxide is responsible for the DNA binding of benzo[ghi]perylene, a polycyclic aromatic hydrocarbon without a “classic” bay-region
2008
Abstract The polycyclic aromatic hydrocarbon (PAH) benzo[ghi]perylene (BghiP) lacks a “classic” bay-region and is therefore unable to form vicinal dihydrodiol epoxides thought to be responsible for the genotoxicity of carcinogenic PAHs like benzo[a]pyrene. The bacterial mutagenicity of BghiP increases considerably after inhibition of the microsomal epoxide hydrolase (mEH) indicating arene oxides as genotoxic metabolites. Two K-region epoxides of BghiP, 3,4-epoxy-3,4-dihydro-BghiP (3,4-oxide) and 3,4,11,12-bisepoxy-3,4,11,12-tetrahydro-BghiP (3,4,11,12-bisoxide) identified in microsomal incubations of BghiP are weak bacterial mutagens in strain TA98 of Salmonella typhimurium with 5.5 and 1.5…
Comparison of enzyme phenotypes in human bladder tumours and experimentally induced hyperplastic and neoplastic lesions of the rat urinary bladder. A…
1988
The expression of a number of enzymes involved in drug metabolism, membrane function etc. was compared in hyperplastic and neoplastic lesions of the rat bladder and in human bladder tumours. Transitional cell carcinomas (TCC) in both rat and Man were characterized by decreased alkaline phosphatase (ALP) and increased gamma-glutamyl transpeptidase (GGT), beta-glucuronidase (beta-G1), succinate dehydrogenase (SD) and glucose-6-phosphate dehydrogenase (G6PD) activities. In addition, binding for antibodies specific for different cytochrome P-450 species (UT50, PB3a, MC1, MC2) and microsomal epoxide hydrolase (mEHb) was elevated in both murine and human tumours. Comparison of the enzyme phenotyp…
The Effect of Indobufen on the Activities of Selected Rat Liver Phase I and Phase II Drug Metabolizing Enzymes, Peroxisomal β-oxidation and Hepatic G…
1994
Abstract Oral administration of indobufen to male rats for three days at daily doses of 5, 10 and 20 mg kg−1 resulted in no changes in liver total glutathione, cytosolic glutathione S-transferases or microsomal epoxide hydrolase. Reduced glutathione appeared slightly diminished to about 84% of control at the highest dose level. Microsomal cytochrome P450-dependent ethoxyresorufin O-de-ethylase and pentoxyresorufin de-alkylase activities were decreased to 64% (not significantly) and 67% of control at the lowest dose level. 6α- and 7α-Hydroxytestosterone activities were decreased to 67 and 68% of control at the highest dose level. Cyanide-insensitive peroxisomal fatty acid β-oxidation was inc…
In vitro modeling of the ternary interaction in juvenile hormone metabolism
1996
The gradual decline in juvenile hormone (JH) titer followed by its complete clearance early in the last larval instar is required for the onset of the metamorphosis of lepidopterous larvae. JH titer is regulated by both biosynthesis and degradation. Two major pathways for JH metabolism, ester hydrolysis and epoxide hydration, are due to JH esterase (JHE) and JH epoxide hydrolase (JHEH), respectively. In vitro experiments designed to elucidate the molecular mechanism of JH metabolism are described. First, microsomal JHEH in Manduca sexta eggs was identified by using photoaffinity analogs of JH, and purified to homogeneity with ion exchange and hydroxylapatite columns. Purified JHEH from M. s…