Carcinogenesis, Vol 19, 867-872, Copyright © 1998 by Oxford University Press
Z Huang, FP Guengerich and LS Kaminsky
The cytochrome P450 (P450) enzymes that catalyse metabolism of the
estrogen, estrone (E1), to the putative carcinogen 16alpha-hydroxy E1
(16alpha-OHE1) in humans were determined. The potential of the most
abundant circulating form of estrogen, estrone 3-sulfate (E1S), to be the
substrate was also investigated. Human liver microsomal sulfatases convert
E1S to E1, an essential prerequisite for formation of 16alpha- OHE1 from
added E1S in this system. E1 metabolism to 16alpha-OHE1 in a panel of 15
human liver microsomal preparations correlated with total P450
concentrations (r2 = 0.63) and with activities associated with P450 forms
CYP3A4 and 3A5 (r2 = 0.72). E1 16alpha-hydroxylase activity in human liver
microsomes was inhibited by 75% by monoclonal anti human CYP3A4/5
antibodies at 4 mg antibody/nmol total P450, and by troleandomycin, a
specific CYP3A4/5 inhibitor. Rates of E1 metabolism to 16alpha-OHE1 were
1.6-fold higher when E1 was generated in situ from E1S than when E1 was
added. Microsomal preparations of cDNA expressed CYP3A4 or 3A5, with
NADPH-P450-reductase co-expressed, both metabolized E1 to 16alpha-OHE1, and
added cytochrome b5 increased the rates 5.1- and 7.5-fold, respectively. In
these systems rates of E1 metabolism to 16alpha-OHE1 were 2.8-fold higher
when E1 was generated in situ from E1S than when E1 was added. Kinetic
values for E1 metabolism to 16alpha- OHE1 by human liver microsomes and for
the expressed CYP3A4 system were Km 154 and 172 microM, respectively, and
Vmax 238 pmol/min/nmol total P450 and 1050 pmol/min/nmol CYP3A4,
respectively. Thus, formation of the putative carcinogen 16alpha-OHE1 is
catalysed by CYP3A4 and 3A5 and stimulated by cytochrome b5. E1S is not a
substrate but formation of E1 from E1S in situ stimulates formation of
16alpha-OHE1, possibly because E1S is more water soluble and in situ
generation of E1 provides for facilitated exposure of E1 to the P450
substrate binding sites. Blocking of the pathway of E1 to 16alpha-OHE1
could provide a therapeutic approach for diminishing the risk of estrogen
dependent breast cancer.
ARTICLES
16Alpha-hydroxylation of estrone by human cytochrome P4503A4/5
Department of Environmental Health and Toxicology, School of Public Health, University at Albany, SUNY, NY 12201-0509, USA.
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