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PubMed2003

Biocompatibility of hydroxylated metabolites of BISGMA and BFDGE.

Unpolymerized dental monomers can leach out into the oral biophase and are bioavailable for metabolism. We hypothesize that metabolites would be less toxic than parent monomers. We first identified the formation of metabolites from bisphenol F diglycidyl ether (BFDGE) and Bisphenol A glycidyl methacrylate (BISGMA) after their exposure to liver S9 fractions. Then, the metabolites and parent compounds were subjected to in vitro cytotoxicity, mutagenicity, and estrogenicity studies. Bisphenol A bis(2,3-dihydroxypropyl) ether and bisphenol F bis(2,3-dihydroxypropyl) ether were the hydroxylated metabolites of BISGMA and BFDGE, respectively. Cytotoxicity against L929 cells showed that the metabolites were significantly (p < 0.05) less cytotoxic than the parent monomers. Only BFDGE was mutagenic in the Ames assay with strain TA100 of Salmonella typhimurium. Parent and metabolite compounds did not stimulate estrogen-dependent MCF-7 cell proliferation above solvent controls. These results indicated that the hydroxylated metabolites were non-mutagenic, non-estrogenic, and less cytotoxic than their parent monomers.

Animals↗
PubMed1999

In vivo formation and localization of 1,1-dichloroethylene epoxide in murine liver: identification of its glutathione conjugate 2-S-glutathionyl acetate.

The hepatotoxic effects induced by 1,1-dichloroethylene (DCE) are ascribed to cytochrome P-450 (CYP) 2E1-dependent formation of metabolites including 2,2-dichloroacetaldehyde and the DCE-epoxide. The DCE metabolites detected in incubations of liver microsomes are the acetal, the hydrate of 2,2-dichloroacetaldehyde, and the epoxide-derived GSH conjugates 2-S-glutathionyl acetyl glutathione ([B]) and 2-S-glutathionyl acetate ([C]). This study was undertaken to determine whether these DCE metabolites are also formed in vivo in murine liver. HPLC analysis of cytosol isolated from the livers of mice treated with [(14)C]DCE showed that [C] was the major conjugate formed, with lower levels of formation of [B]. The acetal was not detected in the cytosol. The formation of the epoxide-derived GSH conjugates was dose-dependent at 25 to 225 mg/kg DCE and occurred coincidentally with levels of covalent binding of DCE at the same doses. The acetal and conjugates [B] and [C] were also detected in bile collected from mice treated with DCE. Pretreatment of mice with buthionine sulfoximine decreased sulfhydryl levels and formation of conjugate [C], and increased DCE binding to liver proteins. In contrast, the levels of [C] and DCE binding were both reduced significantly in mice pretreated with the CYP2E1 inhibitor diallyl sulfone. Immunohistochemical studies indicated that protein adducts and conjugate [C] were localized in centrilobular hepatocytes and corresponded with the sites where CYP2E1 resided. Pretreatment with buthionine sulfoximine increased the amount of immunostaining. However, pretreatment with diallyl sulfone markedly decreased immunostaining for [C] in the hepatocytes. These results showed that 2,2-dichloroacetaldehyde and the epoxide are formed from DCE in vivo.

Allyl Compounds↗
PubMed1998

The butadiene metabolite, 1,2:3,4-diepoxybutane, induces micronuclei but is only weakly mutagenic at lacI in the Big Blue Rat2 lacI transgenic cell line.

1,3-Butadiene (BD) is a genotoxic carcinogen that is bioactivated to at least two mutagenic metabolites, 1,2-epoxybutene (EB) and 1,2:3,4-diepoxybutane (DEB). We investigated the mutagenicity and induction of micronuclei by DEB in vitro in Rat2 lambda/lacI transgenic fibroblasts (Big Blue Rat2 cells, Stratagene, LaJolla, CA). Assays for mutagenicity and micronuclei induction were carried out at concentrations of 0, 2, 5, or 10 microM DEB for 24 hours. Exposure of cells to these concentrations of DEB resulted in approximately 100, 50, and 10% survival, respectively, compared with media controls. In independent replicate experiments, no statistically significant increase in lacI mutant frequency was observed in Rat2 cells at any of the DEB exposure concentrations when compared to media or solvent controls. However, regression analyses indicated a trend toward increasing mutant frequency with increasing DEB exposure concentration. Experiments to examine the induction of micronuclei by DEB revealed a concentration-dependent increase in micronuclei in Rat2 cells following exposure to DEB. These results indicate that DEB induces micronuclei in the absence of detectable gene mutation at lacI in Big Blue Rat2 cells. The induction of micronuclei but only weak mutagenicity at the lacI transgene is likely due to the poor recovery of deletions using this lambda shuttle vector system, demonstrating the need to investigate multiple endpoints of genotoxicity when considering the mutational activity of a compound.

Animals↗
PubMed1979

The binding to mouse skin DNA of benzo[a]pyrene, its 7,8-diol and 7,8-diol-9,10-epoxides in relation to the tumorigenicity of these compounds.

Tritium labelled and carbon-14 labelled benzo[a]pyrene (PB), (+/-)trans 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (PB-7,8-diol), (+/-)-7 alpha,8 beta-dihydroxy-9 beta,10 beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and (+/-)-7 alpha, 8 beta-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]-pyrene were applied to the shaved backs of mice. After 24 h the DNA was isolated from the treated skin and the extent of hydrocarbon binding was determined. The level of DNA binding is considered in relation to the previously reported carcinogenicity of the various benzo[a]pyrene derivatives.

Animals↗
PubMed2004

Regio- and stereospecific cleavage of silyl- and disilylepoxides with lithium diphenylphosphide.

Unsubstituted or alpha- and beta-C-substituted silylepoxides react stereospecifically with lithium diphenylphosphide, optionally followed by methylation, to give vinylphosphonium iodides or vinylphosphine oxides resulting from alpha-opening and silyl enol ethers, vinylsilanes or alpha-hydroxysilanes by beta-opening. On the other hand, alpha,beta- or alpha,alpha-disilylepoxides afforded beta-silyl vinylphosphine oxides or alpha-silylated silyl enol ethers by alpha- and beta-cleavage, respectively. All compounds are interesting synthons in organic chemistry.

Epoxy Compounds↗
PubMed1993

Coated macroporous carriers with oxirane groups and their reactivity.

Macroporous carriers were prepared by coating controlled pore silicas with copolymers of hydroxyalkyl methacrylate and alkaline dimethacrylate activated by epichlorhydrin (140-1000 mumol/g epoxide group content). The relationship between the preparation conditions (the monomer ratio, the nature of the solvent, the method of activation by epichlorhydrin and the reaction temperature) was studied, as well as the surface characteristics responsible for the carrier's ability to bond (the value of the surface area before and after coating with copolymers and the degree of cross-linking required for the accessibility of the reactive groups). The coupling of various amino compounds, ammonia, aminopropanol, 1,2-diaminoethane, 1,6-diaminohexane and, as a model enzyme, alpha chymotrypsin on to derivatized carriers was investigated as a function of pH, reaction time and the concentration of the compound bonded.

Amines↗
PubMed2003

Zinc modulates PPARgamma signaling and activation of porcine endothelial cells.

Dietary zinc has potent antioxidant and anti-inflammatory properties and is a critical component of peroxisome proliferator-activated receptor (PPAR) gene expression and regulation. To assess the protective mechanisms of PPARgamma in endothelial cell dysfunction and the role of zinc in the modulation of PPARgamma signaling, cultured porcine pulmonary artery endothelial cells were exposed to the membrane-permeable zinc chelator N,N,N'N'-tetrakis (2-pyridylmethyl)-ethylene diamine (TPEN), thiazolidinedione (TZD; PPARgamma agonist) or bisphenol A diglycidyl ether (BADGE; PPARgamma antagonist). Subsequently, endothelial cells were activated by treatment with linoleic acid (90 micro mol/L) for 6 h. Zinc chelation by TPEN increased the DNA binding activity of nuclear factor (NF)-kappaB and activator protein (AP)-1, decreased PPARgamma expression and activation as well as up-regulated interleukin (IL)-6 expression and production. These effects were fully reversed by zinc supplementation. In addition, exposure to TZD down-regulated linoleic acid-induced DNA binding activity of NF-kappaB and AP-1, whereas BADGE further induced activation of these oxidative stress-sensitive transcription factors. Most importantly, the TZD-mediated down-regulation of NF-kappaB and AP-1 and reduced inflammatory response were impaired during zinc chelation. These data suggest that zinc plays a critical role in PPARgamma signaling in linoleic acid-induced endothelial cell activation and indicate that PPARgamma signaling is impaired during zinc deficiency.

Animals↗
PubMed1994

Binding of (+)- and (-)-isomers and racemate of etomoxir to human serum albumin and effect of stearic acid and stanozolol.

Binding of (+)- and (-)-isomers and the racemate of sodium 2[6-(4-chlorophenoxy)-hexyl]-oxiran-2-carboxylate dihydrat (etomoxir) to the human serum albumin (HSA) was studied by the gel filtration method. The experimental results are presented graphically using the method of Scatchard. Measurements revealed the following data on the binding: (a) for either of the isomers there are two independent and nonequivalent classes of binding sites on the HSA molecule; (b) the binding constants calculated for both isomers were of the same order of magnitude (K1/n approximately 20 x 10(5) L.mol-1 for the concentration range 3.48-4.0 x 10(-5) mol.L-1, and K2/n approximately 2 x 10(5) L.mol-1 for the concentration range 4.28-10 x 10(-5) mol.L-1, for the high and low affinity binding sites, respectively); (c) statistically significant difference (p < or = 0.05) between the low affinity binding constant estimated for the (+)-isomer K2 = 1.9 +/- 0.1 x 10(5) L.mol-1) compared with the constants evaluated for the (-)-isomer and racemic etomoxir (2.6 +/- 0.1 and 2.9 +/- 0.2 x 10(5) L.mol-1, respectively); and (d) both isomers are bound into a high extent to the HSA molecule (i.e., at a ligand concentration of 3.48 x 10(-5) mol.L-1, the percent of binding was approximately 95% for the compound tested. When plotting the percent binding (% Cb) against the total concentration (Ctot), a statistically significant difference (p < or = 0.05) was obtained between the slope of the straight line for the (+)-isomer and those for other two compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMedDate not supplied

One-pot synthesis of star-shaped macromolecules containing polyglycidol and poly(ethylene oxide) arms.

Synthesis of fully hydrophilic star-shaped macromolecules with different kinds of arms (A(x)B(y)C(z)) based on polyglycidol (PGL, A(x)) and poly(ethylene oxide) (PEO, C(z)) arms and diepoxy compounds (diglycidyl ethers of ethylene glycol (DGEG) or neopentyl glycol (DGNG) in the core, B(y)) forming the core is described. Precursors of arms were prepared by polymerization of glycidol with protected -OH groups. The first-generation stars were formed in the series of consecutive-parallel reactions of arms A(x) with diepoxy compounds (B). These first-generation stars (A(x)B(y)), having approximately O-, Mt+ groups on the cores, were used as multianionic initiators for the second generation of arms (C(z)) built by polymerization of ethylene oxide. The products with M(n) up to 10(5) and having up to approximately 40 arms were obtained. The number of arms (f) was determined by direct measurements of M(n) of the first-generation stars (M(n) of arms A(x) is known), compared with f calculated from the branching index g, determined from R(g) measured with size-exclusion chromatography (SEC) triple detection with TriSEC software. The progress of the star formation was monitored by 1H NMR and SEC. These novel water-soluble stars, having a large number of hydroxyl groups, both at the ends of PEO arms as well as within the PGL arms, can be functionalized and further used for attaching compounds of interest. This approach opens, therefore, a new way of "multiPEGylation".

Chromatography, Gel↗
PubMed1977

Metabolic activation of mycotoxins by animals and humans: an overview.

Aflatoxins are associated with acute toxicoses in poultry and livestock and with liver cancer in human populations in Africa and Southeast Asia. Comparative metabolism studies indicate that aflatoxin B1, the most potent of these compounds, requires metabolic activation to the ultimate carcinogen. The mycotoxin (1) is oxidatively demethylated to form the phenolic derivative, (2) is hydroxylated directly at three sites, and (3) undergoes reduction of the carbonyl group in the cyclopentenone ring to a hydroxyl group; these five hydroxy derivatives all appear to be part of detoxication pathways. Considerable evidence is now available to support the hypothesis that activation of aflatoxin B1 to the ultimate carcinogen involves epoxidation of the double bond in the terminal furan ring. The epoxide decomposes to form a carbonium ion at C-2, which attacks nucleophilic sites in DNA, especially on the guanine moiety. Thus, like carcinogenic polycyclic hydrocarbons and N-nitroso compounds, aflatoxin B1 appears to be activated to an alkylating agent.

Aflatoxins↗
PubMed1977

[The role of cytochrome P450 in the activation of drugs (author's transl)].

Unspecific microsomal monooxygenases have been found in many organisms of different developmental stages. In higher organisms liver is the main organ of drug metabolism but smaller intestine, lung and skin also show this activity. The corresponding membrane-bound enzyme system could be isolated by modern chromatographic techniques and was found to consist of a reductase and a series of cytochrome P450 enzymes. Each of these cytochromes has a different, but with other forms overlapping substrate specificity. The steady-state concentrations of the various forms is regulated by induction with drugs and foreign compounds. The unspecificity of the systems is also reflected in the varying pattern of metabolites. In general stable and more polar metabolites are formed by the monooxygenation reaction, but reactive and unstable products may also appear, e.g. N-hydroxy compounds, 1,2-diphenols, epoxides and a new class of compounds which have been characterized as carbenes.

Adult↗
PubMed2002

Sesquiterpene and long chain ester from Tanacetum longifolium.

A new naturally occurring linear sesquiterpene (tanacetene) (1). having irregular non-head- to- tail attachment of isoprene units, a new long chain ester (2). and 10 known compounds have been isolated from hexane and chloroform extracts of the roots and aerial parts of Tanacetum longifolium wall. The structure of (tanacetene) (1). was established as (2E,6E,10E)-2,6,11-trimethyl-dodeca-2,6,10-triene and that of (2). as heptatriacontanyl eicosanoate by spectroscopic methods along with 10 known compounds. From the oily fraction twelve volatile compounds were identified by GC-MS. The roots of this plant were found to be a new major source of Z-spiroketalenol ether-6,7-epoxy-diyne in 3.2% yield on dry weight basis.

Alkynes↗
PubMed2006

Exploring the S4 and S1 prime subsite specificities in caspase-3 with aza-peptide epoxide inhibitors.

Caspase-3 is a prototypic executioner caspase that plays a central role in apoptosis. Aza-peptide epoxides are a novel class of irreversible inhibitors that are highly specific for clan CD cysteine proteases. The five crystal structures of caspase-3-aza-peptide epoxide inhibitor complexes reported here reveal the structural basis for the mechanism of inhibition and the specificities at the S1' and the S4 subsites. Unlike the clan CA cysteine proteases, the catalytic histidine in caspase-3 plays a critical role during protonation and subsequent ring opening of the epoxide moiety and facilitates the nucleophilic attack by the active site cysteine. The nucleophilic attack takes place on the C3 carbon atom of the epoxide and results in an irreversible alkylation of the active site cysteine residue. A favorable network of hydrogen bonds involving the oxyanion hole, catalytic histidine, and the atoms in the prime site of the inhibitor enhance the binding affinity and specificity of the aza-peptide epoxide inhibitors toward caspase-3. The studies also reveal that subtle movements of the N-terminal loop of the beta-subunit occur when the P4 Asp is replaced by a P4 Ile, whereas the N-terminal loop and the safety catch Asp179 are completely disordered when the P4 Asp is replaced by P4 Cbz group.

Aza Compounds↗
PubMed2002

Aza-peptide epoxides: a new class of inhibitors selective for clan CD cysteine proteases.

Aza-peptide epoxides, a new class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. The inhibitors have second-order rate constants up to 10(5) M(-1) s(-1), with the most potent epoxides having the S,S stereochemistry. The aza-Asn derivatives are effective legumain inhibitors, while the aza-Asp epoxides were specific for caspases. The inhibitors have little or no inhibition with other proteases such as chymotrypsin, papain, or cathepsin B.

Aza Compounds↗