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Vol. 30, Issue 11, 1266-1273, November 2002
Department of Drug Disposition, Lilly Research Laboratories, Eli
Lilly and Company, Indianapolis, Indiana (J.A.W., B.J.R., V.E.C., K.C.,
S.A.W.); and Department of Clinical Pharmacology, Indiana University
School of Medicine, Indianapolis, Indiana (D.R.J., S.D.H.)
Previous results demonstrating homotropic activation of human
UDP-glucuronosyltransferase (UGT) 1A1-catalyzed
estradiol-3-glucuronidation led us to investigate the effects of 16 compounds on estradiol glucuronidation by human liver microsomes (HLM).
In confirmation of previous work using alamethicin-treated HLM pooled
from four livers, UGT1A1-catalyzed estradiol-3-glucuronidation
demonstrated homotropic activation kinetics (S50 = 22 µM, Hill coefficient, n = 1.9) whereas
estradiol-17-glucuronidation (catalyzed by other UGT enzymes) followed
Michaelis-Menten kinetics (Km = 7 µM). Modulatory effects of the following compounds were investigated:
bilirubin, eight flavonoids, 17
-ethynylestradiol (17-EE),
estriol, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), anthraflavic acid, retinoic
acid, morphine, and ibuprofen. Although the classic UGT1A1 substrate
bilirubin was a weak competitive inhibitor of
estradiol-3-glucuronidation, the estrogens and anthraflavic acid
activated or inhibited estradiol-3-glucuronidation dependent on
substrate and effector concentrations. For example, at substrate
concentrations of 5 and 10 µM, estradiol-3-glucuronidation activity
was stimulated by as much as 80% by low concentrations of 17-EE but
was unaltered by flavanone. However, at higher substrate concentrations
(25-100 µM) estradiol-3-glucuronidation was inhibited by about 55%
by both compounds. Anthraflavic acid and PhIP were also stimulators of
estradiol 3-glucuronidation at low substrate concentrations. The most
potent inhibitor of estradiol 3-glucuronidation was the flavonoid
tangeretin. The UGT2B7 substrates morphine and ibuprofen had no effect
on estradiol 3-glucuronidation, whereas retinoic acid was slightly
inhibitory. Estradiol-17-glucuronidation was inhibited by 17-EE,
estriol, and naringenin but was not activated by any compound. This
study demonstrates that the interactions of substrates and inhibitors
at the active site of UGT1A1 are complex, yielding both activation and
competitive inhibition kinetics.
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