248 research outputs found

    The Meta Isomer of Acetaminophen Is A Time Dependent Inhibitor of Human CYP2E1

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    N-acetyl-m-aminophenol (3’-hydroxyacetanilide, AMAP) is the meta isomer of acetaminophen (4’-hydroxyacetanilide, APAP), the widely used analgesic that is safe at therapeutic doses but is hepatotoxic at larger doses. Unlike APAP, AMAP does not cause hepatotoxicity in mice even though AMAP and its metabolites covalently bind to hepatic proteins at levels comparable to APAP. Therefore, comparative studies with APAP and AMAP have been used in order to investigate mechanisms of toxicity and structure-toxicity relationships. However, the relationship between AMAP and CYP2E1, the enzyme generally implicated in the amplification of APAP-induced hepatotoxicity after ethanol ingestion, has not been fully elucidated. The microsomal metabolism of AMAP to reactive metabolites has been studied however, the identity of the reactive metabolite(s) of AMAP that bind to CYP2E1 has not been unequivocally determined. Therefore, we hypothesized that AMAP would covalently bind to and inhibit CYP2E1 in a reconstituted system and that mass spectral analysis would provide structural information for the reactive metabolite. Deconvoluted mass spectra indicated that a reactive metabolite of AMAP forms mono- and diadducts with CYP2E1 apoprotein (experimentally measured masses = 54622.4 ± 8.9 Da, 54791.3 ± 6.1 Da, and 54451.7 ± 5.5 Da, respectively) but not to other incubation components (i.e., heme, cytochrome b5, or cytochrome P450 reductase). NADPH was required for adduct formation while glutathione prevented it. The data indicated that reactive metabolite formation probably involves the addition of one oxygen atom to AMAP (MWAMAP = 151.2 Da; MWoxidized AMAP = 151.2 + 16.0 = 167.2 Da; experimentally determined mass of the small molecule adducted to CYP2E1 = 167.5 ± 7.1 Da. Therefore, the reactive metabolite of AMAP that covalently binds to CYP2E1 is likely formed from aromatic oxidation (quinone formation)

    Ethanol and production of the hepatotoxic metabolite of acetaminophen in healthy adults

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    Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109855/1/cptclpt200062.pd

    Controlling roadside garbage dumping in rural Oklahoma

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    The Oklahoma Cooperative Extension Service periodically issues revisions to its publications. The most current edition is made available. For access to an earlier edition, if available for this title, please contact the Oklahoma State University Library Archives by email at [email protected] or by phone at 405-744-6311

    Signatures of arithmetic simplicity in metabolic network architecture

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    Metabolic networks perform some of the most fundamental functions in living cells, including energy transduction and building block biosynthesis. While these are the best characterized networks in living systems, understanding their evolutionary history and complex wiring constitutes one of the most fascinating open questions in biology, intimately related to the enigma of life's origin itself. Is the evolution of metabolism subject to general principles, beyond the unpredictable accumulation of multiple historical accidents? Here we search for such principles by applying to an artificial chemical universe some of the methodologies developed for the study of genome scale models of cellular metabolism. In particular, we use metabolic flux constraint-based models to exhaustively search for artificial chemistry pathways that can optimally perform an array of elementary metabolic functions. Despite the simplicity of the model employed, we find that the ensuing pathways display a surprisingly rich set of properties, including the existence of autocatalytic cycles and hierarchical modules, the appearance of universally preferable metabolites and reactions, and a logarithmic trend of pathway length as a function of input/output molecule size. Some of these properties can be derived analytically, borrowing methods previously used in cryptography. In addition, by mapping biochemical networks onto a simplified carbon atom reaction backbone, we find that several of the properties predicted by the artificial chemistry model hold for real metabolic networks. These findings suggest that optimality principles and arithmetic simplicity might lie beneath some aspects of biochemical complexity

    LSST Science Book, Version 2.0

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    A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

    Silencing and Un-silencing of Tetracycline-Controlled Genes in Neurons

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    To identify the underlying reason for the controversial performance of tetracycline (Tet)-controlled regulated gene expression in mammalian neurons, we investigated each of the three components that comprise the Tet inducible systems, namely tetracyclines as inducers, tetracycline-transactivator (tTA) and reverse tTA (rtTA), and tTA-responsive promoters (Ptets). We have discovered that stably integrated Ptet becomes functionally silenced in the majority of neurons when it is inactive during development. Ptet silencing can be avoided when it is either not integrated in the genome or stably-integrated with basal activity. Moreover, long-term, high transactivator levels in neurons can often overcome integration-induced Ptet gene silencing, possibly by inducing promoter accessibility
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