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Vol. 300, Issue 3, 838-849, March 2002
Department of Basic Pharmaceutical Sciences, College of Pharmacy,
University of South Carolina, Columbia, South Carolina (A.J.L., L.H.M.,
J.W.K., B.T.Z.); and Department of Chemical Biology, College of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New
Jersey (A.H.C.)
We characterized the NADPH-dependent metabolism of estrone
(E1) by liver microsomes of 21 male and 12 female human
subjects. The structures of 11 hydroxylated or keto metabolites of
E1 formed by human liver microsomes were identified by
chromatographic and mass spectrometric analyses. 2-Hydroxylation of
E1 was the dominant metabolic pathway with all human liver
microsomes tested. E1 is more prone to form catechol
estrogens (particularly 4-OH-E1) than 17
-estradiol (E2) and the average ratio of
E1 4-hydroxylation to 2-hydroxylation (0.24) was slightly
higher than the ratio of E2 4- to 2-hydroxylation (0.20, P < 0.001). An unidentified monohydroxylated E1 metabolite (y-OH-E1) was
found to be one of the major metabolites formed by human liver
microsomes of both genders. 6-OH-E1,
16
-OH-E1, and 16-OH-E1 were also formed
in significant quantities. 16-Hydroxylation was not a major pathway
for E1 metabolism. The overall profiles for the
E1 metabolites formed by male and female human liver
microsomes were similar, and their average rates were not significantly
different. Hepatic CYP3A4/5 activity in both male and female liver
microsomes correlated strongly with the rates of formation of several
hydroxyestrogen metabolites. The dominant role of hepatic CYP3A4 and
CYP3A5 in the formation of these hydroxyestrogen metabolites was
further confirmed by incubations of human CYP3A4 or CYP3A5 with
[3H]E1 and NADPH. Notably, human CYP3A5 has
very high relative activity for E1 4-hydroxylation,
exceeding its activity for E1 2-hydroxylation by ~100%.
It will be of interest to determine the potential biological functions
associated with any of the E1 metabolites identified in our
present study.
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