250 research outputs found
The Meta Isomer of Acetaminophen Is A Time Dependent Inhibitor of Human CYP2E1
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)
Metabolism of [p-180]-Phenacetin: The Mechanism of Activation of Phenacetin to Reactive Metabolites in Hamsters
Ethanol and production of the hepatotoxic metabolite of acetaminophen in healthy adults
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109855/1/cptclpt200062.pd
Controlling roadside garbage dumping in rural Oklahoma
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
Association Between Raised Blood Pressure and Dysglycemia in Hong Kong Chinese
OBJECTIVE—To investigate the association between raised blood pressure and dysglycemia
Signatures of arithmetic simplicity in metabolic network architecture
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
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
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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