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Characterization of the Oxidative Metabolites of 17ß-Estradiol and Estrone Formed by 15 Selectively Expressed Human Cytochrome P450 Isoforms

Department of Basic Pharmaceutical Sciences (A.J.L., B.T.Z.), College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208; and Susan Lehman Cullman Laboratory for Cancer Research (M.X.C., P.E.T., A.H.C.), Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854

Address all correspondence and requests for reprints to: Bao Ting Zhu, Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208. E-mail: BTZhu{at}cop.sc.edu.

We systematically characterized the oxidative metabolites of 17ß-estradiol and estrone formed by 15 human cytochrome P450 (CYP) isoforms. CYP1A1 had high activity for 17ß-estradiol 2-hydroxylation, followed by 15-, 6-, 4-, and 7-hydroxylation. However, when estrone was the substrate, CYP1A1 formed more 4-hydroxyestrone than 15- or 6-hydroxyestrone, with 2-hydroxyestrone as the major metabolite. CYP1A2 had the highest activity for the 2-hydroxylation of both 17ß-estradiol and estrone, although it also had considerable activity for their 4-hydroxylation (9–13% of 2-hydroxylation). CYP1B1 mainly catalyzed the formation of catechol estrogens, with 4-hydroxyestrogens predominant. CYP2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 each showed a varying degree of low catalytic activity for estrogen 2-hydroxylation, whereas CYP2C18 and CYP2E1 did not show any detectable estrogen-hydroxylating activity. CYP3A4 had strong activity for the formation of 2-hydroxyestradiol, followed by 4-hydroxyestradiol and an unknown polar metabolite, and small amounts of 16- and 16ß-hydroxyestrogens were also formed. The ratio of 4- to 2-hydroxylation of 17ß-estradiol or estrone with CYP3A4 was 0.22 or 0.51, respectively. CYP3A5 had similar catalytic activity for the formation of 2- and 4- hydroxyestrogens. Notably, CYP3A5 had an unusually high ratio of 4- to 2-hydroxylation of 17ß-estradiol or estrone (0.53 or 1.26, respectively). CYP3A4 and 3A5 also catalyzed the formation of nonpolar estrogen metabolite peaks (chromatographically less polar than estrone). CYP3A7 had a distinct catalytic activity for the 16-hydroxylation of estrone, but not 17ß-estradiol. CYP4A11 had little catalytic activity for the metabolism of 17ß-estradiol and estrone. In conclusion, many human CYP isoforms are involved in the oxidative metabolism of 17ß-estradiol and estrone, with a varying degree of catalytic activity and distinct regioselectivity.

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