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    Metabolism and Toxicity of Thioacetamide and Thioacetamide SOxide in Rat Hepatocytes

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    Issue Date
    2012-09-17
    Author
    Hajovsky, Liz
    Hu, Gang
    Koen, Yakov M.
    Sarma, Diganta
    Cui, Wenqi
    Moore, David S.
    Staudinger, Jeffrey Leonard
    Hanzlik, Robert P.
    Publisher
    ACS
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    © 2012 American Chemical Society
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    Abstract
    The hepatotoxicity of thioacetamide (TA) has been known since 1948. In rats, single doses cause centrilobular necrosis accompanied by increases in plasma transaminases and bilirubin. To elicit these effects TA requires oxidative bioactivation leading first to its S-oxide (TASO) and then to its chemically reactive S,S-dioxide (TASO2) which ultimately modifies amine-lipids and proteins. To generate a suite of liver proteins adducted by TA metabolites for proteomic analysis, and to reduce the need for both animals and labeled compounds, we treated isolated hepatocytes directly with TA. Surprisingly, TA was not toxic at concentrations up to 50 mM for 40 hr. On the other hand, TASO was highly toxic to isolated hepatocytes as indicated by LDH release, cellular morphology and vital staining with Hoechst 33342/propidium iodide. TASO toxicity was partially blocked by the CYP2E1 inhibitors diallyl sulfide and 4-methylpyrazole, and was strongly inhibited by TA. Significantly, we found that hepatocytes produce TA from TASO relatively efficiently by back-reduction. The covalent binding of [14C]-TASO is inhibited by unlabeled TA which acts as a “cold-trap” for [14C]-TA and prevents its re-oxidation to [14C]-TASO. This in turn increases the net consumption of [14C]-TASO despite the fact that its oxidation to TASO2 is inhibited. The potent inhibition of TASO oxidation by TA, coupled with the back-reduction of TASO and its futile redox cycling with TA may help explain phenomena previously interpreted as “saturation toxicokinetics” in the in vivo metabolism and toxicity of TA and TASO. The improved understanding of the metabolism and covalent binding of TA and TASO facilitates the use of hepatocytes to prepare protein adducts for target protein identification.
    Description
    “This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical Research in Toxicology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/tx3002719
    URI
    http://hdl.handle.net/1808/24004
    DOI
    https://doi.org/10.1021/tx3002719
    Collections
    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Hajovsky, L., Hu, G., Koen, Y., Sarma, D., Cui, W., Moore, D. S., … Hanzlik, R. P. (2012). Metabolism and Toxicity of Thioacetamide and Thioacetamide S-Oxide in Rat Hepatocytes. Chemical Research in Toxicology, 25(9), 1955–1963. http://doi.org/10.1021/tx3002719

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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