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PubMedDate not supplied

Regulation of glucose utilization by inhibition of mitochondrial fatty acid uptake in cardiac cells.

In order to investigate the mechanism by which fatty acid oxidation inhibitors regulate cardiac metabolism, the effects of 2-tetradecylglycidic acid (2-TDGA), and 2-bromopalmitic acid (2-BPA) on the oxidation of [1-14C]palmitate, [1-14C]octanoate and [U-14C]glucose were studied in isolated rat myocytes. Fifty per cent inhibition of palmitate oxidation was achieved at 20 microM 2-TDGA and 60 microM 2-BPA. Octanoate oxidation was also inhibited by 2-BPA. In contrast to their effect on palmitate oxidation, fatty acid inhibitors significantly stimulated the oxidation of glucose in a concentration-dependent manner. Moreover, the oxidation of [2-14C]pyruvate was increased two-fold by these compounds. The rate of uptake of [U-14C]-2-deoxyglucose was also stimulated two-fold by these inhibitors. These studies suggest that the stimulation of glucose utilization via the inhibition of fatty acid oxidation may be mediated through the stimulation of both glucose transport and the oxidation of pyruvate by the pyruvate dehydrogenase complex.

Animals↗
PubMed1995

Disposition of butadiene monoepoxide and butadiene diepoxide in various tissues of rats and mice following a low-level inhalation exposure to 1,3-butadiene.

1,3-Butadiene (BD), a chemical used extensively in the production of styrene-butadiene rubber, is carcinogenic in Sprague-Dawley rats and B6C3F1 mice. Chronic inhalation studies revealed profound species differences in the potency and organ-site specificity of BD carcinogenesis between rats and mice. BD is a potent carcinogen in mice and a weak carcinogen in rats. Previous studies from our laboratory and others have shown marked differences between rats and mice in the metabolism of BD, which may account for species differences in carcinogenicity. The purpose of the present study was to examine the production and disposition of two mutagenic BD metabolites, butadiene monoepoxide (BDO) and butadiene diepoxide (BDO2), in blood and other tissues of rats and mice during and following inhalation exposures to a target concentration of 62.5 p.p.m. BD. BDO was increased above background in blood, bone marrow, heart, lung, fat, spleen and thymus tissues of mice after 2 h and 4 h exposures to BD. In rats, levels of BDO were increased in blood, fat, spleen and thymus tissues. No increases in BDO were observed in rat lungs. BDO2, the more mutagenic of the two epoxides, was increased in the blood of rats and mice at 2 and 4 h after initiation of exposure to BD. In mice, BDO2 was detected in all tissues examined immediately following the 4 h exposure. This metabolite was detected in heart, lung, fat, spleen and thymus of rats, but at levels 40- to 160-fold lower than those seen in mice. Immediately after the 4 h exposure, blood levels of BDO2 were 204 +/- 15 pmol/g for mice but were 41-fold lower for rats. In the sensitive mouse target organs, heart and lungs, levels of BDO2 exceeded BDO levels immediately after the exposure. This study shows that the levels of BD epoxides are markedly greater in the mouse BD target organs. The high concentrations of BDO2 in these organs suggest that this compound may be particularly important in BD-induced carcinogenesis. Thus, although BD is oxidatively metabolized by similar metabolic pathways in rats and mice, the substantial quantitative differences in tissue levels of mutagenic epoxides between species may be responsible for the increased sensitivity of mice to BD-induced carcinogenicity.

Administration, Inhalation↗
PubMed2005

Inhibition of efflux transporter-mediated fungicide resistance in Pyrenophora tritici-repentis by a derivative of 4'-hydroxyflavone and enhancement of fungicide activity.

Populations of the causal agent of wheat tan spot, Pyrenophora tritici-repentis, that are collected from fields frequently treated with reduced fungicide concentrations have reduced sensitivity to strobilurin fungicides and azole fungicides (C14-demethylase inhibitors). Energy-dependent efflux transporter activity can be induced under field conditions and after in vitro application of sublethal amounts of fungicides. Efflux transporters can mediate cross-resistance to a number of fungicides that belong to different chemical classes and have different modes of action. Resistant isolates can grow on substrata amended with fungicides and can infect plants treated with fungicides at levels above recommended field concentrations. We identified the hydroxyflavone derivative 2-(4-ethoxy-phenyl)-chromen-4-one as a potent inhibitor of energy-dependent fungicide efflux transporters in P. tritici-repentis. Application of this compound in combination with fungicides shifted fungicide-resistant P. tritici-repentis isolates back to normal sensitivity levels and prevented infection of wheat leaves. These results highlight the role of energy-dependent efflux transporters in fungicide resistance and could enable a novel disease management strategy based on the inhibition of fungicide efflux to be developed.

ATP-Binding Cassette Transporters↗
PubMed2002

[Functional genomics of pressure-loaded cardiomyocytes: etomoxir in heart failure?].

BACKGROUND: Drugs for counteracting the neuroendocrine activation in heart failure can reduce the adverse remodelling of the extracellular matrix of the heart. Progression of heart failure can, however, often not be prevented and the question arises whether important pharmacological targets remain unidentified. Promising are drugs targeted at ventricular diastolic dysfunction which is a marker of early progression of heart failure. PATHOPHYSIOLOGY: Left ventricular dysfunction is characteristic of overloaded hypertrophied hearts with molecular structures that are not adapted to the increased Ca2+ diffusion distances. Thus, the Ca(2+)-pump (SERCA2) of sarcoplasmic reticulum is inadequately expressed leading to a reduced force development and relaxation of hypertrophied cardiomyocytes. ETOMOXIR: Drugs in development (CPT-1 inhibitor/PPARalpha activator) that increase glucose oxidation can enhance SERCA2 expression. The lead compound etomoxir had a selective influence on the contraction and relaxation rate of pressure-overloaded hearts. The functional parameters were correlated with the proportion of alpha-myosin heavy chains. Since viral or inflammatory injury of the heart can also induce a fetal phenotype, metabolic modulators such as etomoxir represent a promising therapeutic approach also for cardiomyopathies with inadequate SERCA2 expression.

Animals↗
PubMed1997

Micronucleus induction in germ and somatic cells of the mouse after exposure to the butadiene metabolites diepoxybutane and epoxybutene.

The genotoxicity of diepoxibutane (DEB) and epoxybutene (EB), two of the main metabolites of 1,3-butadiene, was tested in the germ and somatic cells of the mouse by applying an MN assay in early spermatids, and in peripheral blood reticulocytes of a subgroup of the same animals. DEB (0.17 and 0.35 mmol/kg) and EB (0.35, 0.70 and 1.04 mmol/kg) were administered i.p. In the germ cell assay, significant increases of MN were observed after treatment of premeiotic S-phase cells with both butadiene metabolites, but DEB was shown to be more powerful than EB in the induction of chromosomal damage. A weak effect of the same compounds was also found after treatment of late spermatocytes, approaching the meiotic divisions. From the MN assay in peripheral blood reticulocytes, a statistically significant increase of the frequency of MN was detected at each dose tested for both chemicals. However, the results have again shown that DEB is much more efficient than EB in inducing chromosome damage.

Animals↗
PubMed2002

Iodine(V) reagents in organic synthesis. Part 2. Access to complex molecular architectures via Dess-Martin periodinane-generated o-imidoquinones.

o-Imidoquinones, a rather rare class of compounds, are prepared from anilides by the action of Dess-Martin periodinane (DMP) and water. Their chemistry has been extensively investigated and found to lead to p-quinones and polycyclic systems of diverse molecular architectures. Applications of this methodology to the total synthesis of the naturally occurring compounds, epoxyquinomycin B and BE-10988, are described. Finally, another rare chemical entity, the ketohydroxyamide moiety, has been accessed through this DMP-based synthetic technology, and its reactivity has been studied. Among its most useful reactions is a set of cascade heterocyclic annulations leading to a variety of polycyclic systems of possible biological relevance.

Alkenes↗
PubMed1984

Possible involvement of a vicinal, non-bay-region dihydrodiol-epoxide in the activation of dibenzo[a,e]fluoranthene into bacterial mutagens.

Dibenzo[a,e]fluoranthene, its 7-hydroxy, 3,4- and 12,13-dihydrodiol metabolic derivatives as well as three synthetic, structurally related hydrocarbons, were tested for mutagenicity towards Salmonella typhimurium TA100 strain in the presence of 3-methylcholanthrene-treated rat and mouse liver post-mitochondrial supernatants. Of these compounds, the 12,13-dihydrodiol showed the highest activity, being 6-10 times more mutagenic than the parent compound. Our data, in conjunction with those of previous studies on the liver microsomal metabolism and DNA binding of dibenzo[a,e]fluoranthene and its dihydrodiols, indicate that activation of dibenzo[a,e]fluoranthene to bacterial mutagens may occur predominantly through a vicinal, non-bay-region 12,13-dihydrodiol epoxide.

Animals↗
PubMed1994

Chlorosilphanol A and silphanepoxol, labdane diterpenes from Silphium perfoliatum.

Two carterochaetols, chlorosilphanol A and silphanepoxol, isolated from the leaves of Silphium perfoliatum were assigned structures 1 and 3, respectively, from spectral studies and with absolute stereochemistry established by X-ray crystallography of 1. Complete 1H- and 13C-nmr assignments for the parent compounds and their acetates 2 and 4 were made at high-field using 1D and 2D methods, and chlorosilphanol A was chemically converted via its acetate to silphanepoxol. Revision of structure for related carterochaetols in the literature is required, in particular with respect to the stereochemistry at C-12 and that of the side-chain.

Chlorohydrins↗
PubMed2000

Epolactaene, a novel neuritogenic compound in human neuroblastoma cells, selectively inhibits the activities of mammalian DNA polymerases and human DNA topoisomerase II.

We chemically synthesized epolactaene, a neuritogenic compound in human neuroblastoma cells, and investigated its biochemical action in vitro. Epolactaene and its derivatives selectively inhibited the activities of mammalian DNA polymerase alpha and beta and human DNA topoisomerase II, with IC(50) values of 25, 94, and 10 microM, respectively. By comparison with its structural derivatives, the long alkyl side chain in epolactaene seemed to have an important role in this inhibitory effect. The compound did not influence the activities of plant or prokaryotic DNA polymerases or of other DNA metabolic enzymes such as telomerase, RNA polymerase, and deoxyribonuclease I. Epolactaene did not intercalate into DNA. These results suggested that the neuritogenic compound epolactaene influences both DNA polymerases and topoisomerase II despite the dissimilarity in both structure and properties of these two enzymes and that inhibition of these enzymes could be related to the neuritogenic effect in human neuroblastoma cells. The relationship between the neuritogenic mechanism and cell cycle regulation by epolactaene was also discussed.

Animals↗
PubMed1983

Effects of 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate on fatty acid and glucose metabolism in perfused rat hearts determined using iodine-125 16-iodohexadecanoate.

Long-chain fatty acid oxidation by the isolated perfused rat heart was assayed by external counting using [125I]16-iodohexadecanoic acid as substrate after administration of the hypoketonemic and hypoglycemic compound 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate to rats. Glucose metabolism was also assessed by measuring release of tritium from [2-T]glucose. The oxidation of long chain fatty acids was virtually suppressed in hearts from fed or starved rats given 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate while glucose utilization was increased 2-2.5 fold.

Animals↗
PubMed1979

Metabolism of beta-adrenergic antagonists. Evidence for an arene oxide-NIH shift pathway in the aromatic hydroxylation of oxprenolol.

The metabolic hydroxylation of 4'-deuteriooxprenolol [1-(isopropylamino)-3-[2'-(allyloxy)-4'-deuteriophenoxy]-2-propanol] prepared from the 4'-bromo compound was examined in the rat (in vivo). GC-MS analysis of the 4'-and 5'-hydroxyoxprenolol obtained showed 65% retention of deuterium in each of the metabolites. The results indicate that an arene oxide-NIH shift pathway is operative in these hydroxylation processes. The equal magnitude of deuterium retention is supportive of a 4',5'-arene oxide as a major contributor to their formation.

Animals↗
PubMed2000

Synthesis, structure proof, and biological activity of epothilone cyclopropanes.

[structure--see text] A semisynthetic route to epothilone cyclopropanes from epothilones A and B is described. Of significance, the deoxygenation of the 12, 13-epoxide to give the corresponding olefin was achieved with high efficiency. The title compounds (8, 9) were active in both tubulin polymerization and cytotoxicity assays, which is in direct contrast to a previously published report. These results provide further evidence that the role of the 12,13-epoxide of epothilones is largely conformational and argue against some of the current pharmacophore models.

Antineoplastic Agents↗
PubMedDate not supplied

Formation of 1,N2- and N2,3-ethenoguanine from 2-halooxiranes: isotopic labeling studies and isolation of a hemiaminal derivative of N2-(2-oxoethyl)guanine.

Vinyl halides are oxidized to 2-halooxiranes, which rapidly rearrange to 2-haloacetaldehydes. Both of these species can react with DNA to generate a variety of adducts, including the potentially mutagenic etheno (epsilon) products. 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. Assignments of the NMR shifts of the etheno protons of 1,N2- and N2,3-epsilon-Gua were made with the use of 15N labeling and nuclear Overhauser effects, in revision of the literature. The H-5 proton of N2,3-epsilon-Gua showed facile exchange in acid or base; the H-7 proton of 1,N2-epsilon-Gua was exchanged at neutral or basic pH but not in acid. Reaction of Br2CHCH2OH (labeled at C1 with 2H or 13C) with Guo yielded 1,N2-epsilon-Gua and N2,3-epsilon-Gua, presumably through the intermediacy of 2-bromooxirane. 1H NMR analysis indicated that the labeled carbon was attached to the original Guo N2 atom in both cases. When N2-(2-oxoethyl)Gua was generated from a diethyl acetal or from a glycol, the major product was the cyclic derivative 5,6,7,9-tetrahydro-7-hydroxy-9-oxoimidazo[1,2-alpha]purine. This compound was also formed in considerable yield from the reaction of 2-chlorooxirane with Guo, dGuo 5'-phosphate, or DNA and is relatively stable in the presence of acid or mild base. It does not appear to be readily dehydrated to yield the etheno adducts but may be of significance as a DNA adducts in its own right.

Alcohol Dehydrogenase↗
PubMed2000

Biotransformation of styrene in mice. Stereochemical aspects.

Biotransformation of styrene and its toxic metabolite, phenyloxirane (1), in mice in vivo was studied. Mice were treated with single intraperitoneal doses of styrene (400 mg/kg of body weight), and with (R)-, (S)-, or racemic styrene oxide (150 mg/kg of body weight). Profiles of neutral and acidic metabolites were determined by GC/MS. Mandelic acid (3) and two mercapturic acids, N-acetyl-S-(2-hydroxy-2-phenylethyl)cysteine (5) and N-acetyl-S-(2-hydroxy-1-phenylethyl)cysteine (6), were found to be major urinary metabolites of both styrene and phenyloxirane. 1-Phenylethane-1,2-diol (2) was the main neutral metabolite. The rate of excretion of this metabolite, as determined by GC, was 5-10 times lower than that of mandelic acid. Several minor acidic metabolites were also identified. Among them, novel phenolic metabolites, namely, 2-(4-hydroxyphenyl)ethanol (7), (4-hydroxyphenyl)acetic acid (11), and two isomeric hydroxymandelic acids (12), are of toxicological significance. Main stereogenic metabolites were isolated as methyl esters from extracts of pooled acidified urine treated with diazomethane. The mandelic acid that was obtained was converted to diastereomeric Mosher's derivatives prior to analysis by NMR. Mercapturic acids were analyzed directly by (13)C NMR. Pure enantiomers of 1 were metabolized predominantly but not exclusively to corresponding enantiomers of 3. Styrene yielded predominantly (S)-mandelic acid. Fractions of mercapturic acids 5 and 6 isolated from urine amounted to 12-15% of the dose for all compounds that were administered. Conversion to mercapturic acids was highly regio- and stereoselective, yielding predominantly regioisomer 5. Styrene, as compared to racemic phenyloxirane, yielded slightly more diastereomers arising from (S)-1 than from (R)-1. These data can be explained by formation of a moderate excess of the less mutagenic (S)-1 in the metabolic activation of styrene in mice in vivo.

Acetylcysteine↗
PubMed1994

Regulation of glucose utilization during the inhibition of fatty acid oxidation in rat myocytes.

The study of the regulation of glucose utilization by inhibition of fatty acid oxidation is greatly enhanced by the availability of specific inhibitors of fatty acid oxidation. This study examines the regulation of cardiac glucose utilization by inhibition of fatty acid oxidation at different sites. The effects of Etomoxir and 4-bromocrotonic acid (4-BCA) on the oxidation of [1-14C]palmitate, [1-14C]-octanoate and [U-14C]glucose were studied in isolated rat myocytes. Fifty percent inhibition of palmitate oxidation was achieved at 8 microM Etomoxir and 40 microM 4-BCA. Octanoate oxidation was inhibited only by 4-BCA. In contrast to their effect on palmitate oxidation, these inhibitors significantly stimulated the oxidation of glucose in a concentration-dependent manner. Moreover, the oxidation of [2-14C]pyruvate was increased two-fold by these compounds. The rate of utilization of [U-14C]-2-deoxyglucose was also stimulated 2-3 times by these inhibitors. These studies suggest that the stimulation of glucose utilization via the inhibition of fatty acid oxidation may be mediated through the stimulation of both glucose transport and the oxidation of pyruvate by the pyruvate dehydrogenase complex.

Animals↗
PubMed1981

Preparation of polysaccharide derivatives containing amino groups for application in affinity chromatography.

We describe here simple methods to introduce spacer arms with amino functional group into polysaccharides. (Formula: see text) The technique includes the following steps: Compounds comprising epoxide group(s) are introduced into polymer supports to form the spacers. Then, reactive groups on the other side of the introduced spacers are reacted with ammonia. Since spacers are attached via ether linkage to the supports, the escape of ligands from specific sorbents can be prevented. Moreover, no charged groups arise on the carrier during the activation procedure, thus decreasing the nonspecific protein retention.

Ammonia↗
PubMed1994

Mutagenicity of butadiene and its epoxide metabolites: II. Mutational spectra of butadiene, 1,2-epoxybutene and diepoxybutane at the hprt locus in splenic T cells from exposed B6C3F1 mice.

The mutagenic potential and mutational spectra of butadiene (BD), 1,2-epoxybutene (EB), and diepoxybutane (DEB) were determined in splenic T cells from exposed B6C3F1 mice. Mice exposed by inhalation to 625 p.p.m. BD for 2 weeks displayed an average hprt- mutation frequency of 6.2 x 10(-6) compared to 1.2 x 10(-6) in controls. Mice were also given three daily i.p. doses of 60, 80 and 100 mg EB/kg or 7, 14 and 21 mg DEB/kg. Average hprt- frequencies of 5.4 x 10(-6), 4.1 x 10(-6) and 8.6 x 10(-6) were seen in the EB groups, respectively, while average frequencies of 4.6 x 10(-6), 9.4 x 10(-6) and 13 x 10(-6) were seen in the DEB groups. DNA sequencing revealed that approximately half of the mutations induced in vivo by BD, EB and DEB were frameshift mutations. A +1 frameshift 'hotspot' in six consecutive guanine bases in exon 3 was observed with all three compounds. The remaining mutations produced by BD, EB and DEB were transition and transversion mutations at both AT and GC base pairs. Base pair substitutions induced by BD were biased in favor of mutation at AT base pairs. The mutational spectra produced by BD, EB and DEB were very similar to that observed previously with ethylene oxide, suggesting that these epoxide agents may be working through a similar mutagenic mechanism.

Animals↗
PubMed1992

Comparative studies on the neuro- and reproductive toxicity of acrylamide and its epoxide metabolite glycidamide in the rat.

The neurotoxicity of acrylamide (AA) has been the subject of extensive studies at the morphological and functional levels in both animals and man. The concern for human exposure to monomeric AA derives partly from its extensive use in molecular biology laboratories where, in the United States alone, 100,000-200,000 persons are potentially exposed. Initial work in this laboratory aiming at the development of techniques for using hemoglobin adducts as biomarkers for human exposure to AA, revealed the formation of glycidamide as a reactive epoxide metabolite of acrylamide in the rat (Chem. Res. Toxicol. 3, 406, 1990). In rats treated with 0-100 mg/kg of AA significant dose-rate effects were observed on adduct formation by both AA and glycidamide. The high rate of formation of the metabolite, especially at low doses where approximately 60% of AA was converted to glycidamide in vivo, prompted us to investigate its potential role in the induction of neurotoxic and reproductive effects attributed to AA exposure. In initial neurotoxicological experiments, the effects of the parent compound (8-14 days, 25 and 50 mg/kg/day) and the metabolite (8-14 days, 50 and 100 mg/kg/day) were compared. While at the higher dose both compounds affected the rats' performance on the rotarod, only acrylamide had a significant effect in the hindlimb splay test, which is considered a more sensitive indicator of peripheral neuropathy. On the other hand, a stronger effect was seen for glycidamide than for AA on the male reproductive system, especially on sperm cell viability.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylamide↗