Characterisation of the xenobiotic inhibition selectivity of human UPD-glucuronosyltransferase: PO-351

Verawan Uchaipichat, Leanne Winner, David Elliot, Peter Mackenzie, John Miners

    Research output: Contribution to conferencePaper

    Abstract

    Enzymes of the UDP-glucuronosyltransferase (UGT) superfamily
    catalyse the glucuronidation of structurally diverse xenobiotics
    and endogenous compounds. However, compared to other drug
    metabolising enzymes, the substrate selectivity of the individual
    UGTs (‘isoforms’) is poorly understood, due largely to the limited
    availability of isoform selective inhibitors. Selective inhibitors
    allow identification of the isoform(s) responsible for the metabolism
    of any given compound by human liver microsomes (‘reaction
    phenotyping’). This study was performed to characterise the
    selectivity of inhibition of human UGT isoforms by seven compounds
    [amitriptyline (AM), fluconazole (FZ), hecogenin (HG),
    phenylbutazone (PZ), quinidine (QD), quinine (QN) and sulfinpyrazone
    (SF)] previously reported to inhibit drug glucuronidation
    in vitro or in vivo. UGT 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9,
    1A10, 2B7 and 2B15 were stably expressed in HEK293 cells and
    inhibition by the various compounds was assessed using the nonselective
    UGT substrate 4-methylumbelliferone for all isoforms,
    except UGT1A4. Trifluoperazine was utilised as the substrate
    ‘probe’ for UGT1A4. AM and QD were nonselective inhibitors of
    human UGT activity, while QN inhibited all UGT isoforms
    screened except for UGT 1A6 and 1A9. Adegree of selectivity was
    observed for PZ and SF; IC50 values were lower for inhibition
    of UGT1A family isoforms compared to the UGT2B enzymes. In
    contrast to the other compounds screened, HG and FZ exhibited a
    high degree of selectivity. HG inhibited only UGT1A4 with an
    IC50 of 2.5 M, whereas FZ inhibited only UGT2B7 with an
    IC50 of 1 Mm. Thus, HG and FZ may be valuable for reaction
    phenotyping metabolism by UGT1A4 and UGT2B7, respectively.
    Original languageEnglish
    PagesA142
    Number of pages1
    DOIs
    Publication statusPublished - 2004
    Event8th World Conference on Clinical Pharmacology & Therapeutics incorporating the Annual Scientific Meeting of ASCEPT - Brisbane, Australia
    Duration: 1 Aug 20046 Aug 2004

    Conference

    Conference8th World Conference on Clinical Pharmacology & Therapeutics incorporating the Annual Scientific Meeting of ASCEPT
    CountryAustralia
    CityBrisbane
    Period1/08/046/08/04
    OtherAbstracts published in Pharmacology and Physiology, 31:s, August 2004

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  • Cite this

    Uchaipichat, V., Winner, L., Elliot, D., Mackenzie, P., & Miners, J. (2004). Characterisation of the xenobiotic inhibition selectivity of human UPD-glucuronosyltransferase: PO-351. A142. Paper presented at 8th World Conference on Clinical Pharmacology & Therapeutics incorporating the Annual Scientific Meeting of ASCEPT, Brisbane, Australia. https://doi.org/10.1111/j.1440-1681.2004.cep_4027.pdf.x