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Vol. 298, Issue 2, 420-432, August 2001
-Estradiol to Multiple Metabolites by Human Liver Microsomes
and Selectively Expressed Human Cytochrome P450 3A4 and 3A5
Department of Basic Pharmaceutical Sciences, College of Pharmacy,
University of South Carolina, Columbia, South Carolina (A.J.L., J.W.K.,
B.T.Z.); and Department of Chemical Biology, College of Pharmacy,
Rutgers We characterized the NADPH-dependent metabolism of 17
The State University of New Jersey, Piscataway, New Jersey
(A.H.C.)
-estradiol
(E2) by liver microsomes from 21 male and 12 female human subjects. A large number of radioactive estrogen metabolite peaks were
detected following incubations of [3H]E2 with
male or female human liver microsomes in the presence of NADPH. The
structures of 18 hydroxylated or keto estrogen metabolites formed by
these microsomes were identified by gas chromatography/mass spectrometry analysis. 2-Hydroxylation (the formation of
2-OH-E2 and 2-OH-E1) was the dominant metabolic
pathway with all human liver microsomes tested. The average ratio of
4-OH-E2 to 2-OH-E2 formation was ~1:6. A new
monohydroxylated E2 metabolite (chemical structure
unidentified) was found to be one of the major metabolites formed by
human liver microsomes of both genders. 6-OH-E2 and 16-OH-E2 were also formed in significant quantities, but
products of estrogen 16
-hydroxylation (16-OH-E2 + 16-OH-E1) were quantitatively minor metabolites. In
addition, many other estrogen metabolites such as
6-keto-E2, 6-OH-E2, 7-OH-E2,
12-OH-E2, 15-OH-E2,
15-OH-E2, 16-OH-E1, and
16-keto-E2 were also formed in relatively small quantities.
The overall profiles for the E2 metabolites formed by male
and female human liver microsomes were similar, and their average rates
were not significantly different. The activity of testosterone
6-hydroxylation (a selective probe for CYP3A4/5 activity) strongly
correlated with the rate of formation of 2-OH-E2, 4-OH-E2, and several other hydroxyestrogen metabolites by
both male and female liver microsomes. The dominant role of hepatic CYP3A4 and CYP3A5 in the formation of these hydroxyestrogen metabolites was further confirmed by incubations of selectively expressed human
CYP3A4 or CYP3A5 with [3H]E2 and NADPH.
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