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.
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 language | English |
|---|---|
| Pages | A142 |
| Number of pages | 1 |
| DOIs | |
| Publication status | Published - 2004 |
| Event | 8th World Conference on Clinical Pharmacology & Therapeutics incorporating the Annual Scientific Meeting of ASCEPT - Brisbane, Australia Duration: 1 Aug 2004 → 6 Aug 2004 |
Conference
| Conference | 8th World Conference on Clinical Pharmacology & Therapeutics incorporating the Annual Scientific Meeting of ASCEPT |
|---|---|
| Country/Territory | Australia |
| City | Brisbane |
| Period | 1/08/04 → 6/08/04 |
| Other | Abstracts published in Pharmacology and Physiology, 31:s, August 2004 |