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Vol. 30, Issue 12, 1462-1469, December 2002
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences,
Kanazawa University, Kanazawa, Japan
Troglitazone glucuronidation in human liver and intestine
microsomes and recombinant UDP-glucuronosyltransferases (UGTs) were thoroughly characterized. All recombinant UGT isoforms in
baculovirus-infected insect cells (UGT1A1, UGT1A3, UGT1A4, UGT1A6,
UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15) exhibited
troglitazone glucuronosyltransferase activity. Especially UGT1A8 and
UGT1A10, which are expressed in extrahepatic tissues such as stomach,
intestine, and colon, showed high catalytic activity, followed by
UGT1A1 and UGT1A9. The kinetics of the troglitazone glucuronidation in
the recombinant UGT1A10 and UGT1A1 exhibited an atypical pattern of
substrate inhibition when the substrate concentration was over 200 µM. With a Michaelis-Menten equation at 6 to 200 µM troglitazone,
the Km value was 11.1 ± 5.8 µM and
the Vmax value was 33.6 ± 3.7 pmol/min/mg protein in recombinant UGT1A10. In recombinant UGT1A1, the
Km value was 58.3 ± 29.2 µM and the
Vmax value was 12.3 ± 2.5 pmol/min/mg
protein. The kinetics of the troglitazone glucuronidation in human
liver and jejunum microsomes also exhibited an atypical pattern. The Km value was 13.5 ± 2.0 µM and the
Vmax value was 34.8 ± 1.2 pmol/min/mg for troglitazone glucuronidation in human liver microsomes, and the
Km value was 8.1 ± 0.3 µM and the
Vmax was 700.9 ± 4.3 pmol/min/mg protein in human jejunum microsomes. When the intrinsic clearance was
estimated with the in vitro kinetic parameter, microsomal protein
content, and weight of tissue, troglitazone glucuronidation in human
intestine was 3-fold higher than that in human livers. Interindividual
differences in the troglitazone glucuronosyltransferase activity in
liver microsomes from 13 humans were at most 2.2-fold. The troglitazone
glucuronosyltransferase activity was significantly (r = 0.579, p < 0.05)
correlated with the 
-estradiol 3-glucuronosyltransferase activity,
which is mainly catalyzed by UGT1A1. The troglitazone glucuronosyltransferase activity in pooled human liver microsomes was
strongly inhibited by bilirubin (IC50 = 1.9 µM), a
typical substrate of UGT1A1. These results suggested that the
troglitazone glucuronidation in human liver would be mainly catalyzed
by UGT1A1. Interindividual differences in the troglitazone
glucuronosyltransferase activity in S-9 samples from five human
intestines was 8.2-fold. The troglitazone glucuronosyltransferase
activity in human jejunum microsomes was strongly inhibited by emodin
(IC50 = 15.6 µM), a typical substrate of UGT1A8 and
UGT1A10, rather than by bilirubin (IC50 = 154.0 µM).
Therefore, it is suggested that the troglitazone glucuronidation in
human intestine might be mainly catalyzed by UGT1A8 and UGT1A10.
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