Characterization of the Oxidative Metabolites of 17β-Estradiol and Estrone Formed by 15 Selectively Expressed Human Cytochrome P450 Isoforms
| Autor: | Anthony J. Lee, May Xiaoxin Cai, Allan H. Conney, Paul E. Thomas, Bao Ting Zhu |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Estrone
medicine.drug_class CYP1B1 Metabolite Gene Expression Hydroxylation Transfection Catalysis Substrate Specificity chemistry.chemical_compound Endocrinology Cytochrome P-450 Enzyme System Cytochrome P-450 CYP1A2 Cytochrome P-450 CYP1A1 medicine Cytochrome P-450 CYP3A Humans CYP2A6 Chromatography High Pressure Liquid Estradiol biology Chemistry CYP1A2 Cytochrome P450 Isoenzymes Biochemistry Estrogen Cytochrome P-450 CYP1B1 biology.protein Aryl Hydrocarbon Hydroxylases Oxidation-Reduction NADP |
| Zdroj: | Endocrinology. 144:3382-3398 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2003-0192 |
| Popis: | We systematically characterized the oxidative metabolites of 17beta-estradiol and estrone formed by 15 human cytochrome P450 (CYP) isoforms. CYP1A1 had high activity for 17beta-estradiol 2-hydroxylation, followed by 15alpha-, 6alpha-, 4-, and 7alpha-hydroxylation. However, when estrone was the substrate, CYP1A1 formed more 4-hydroxyestrone than 15alpha- or 6alpha-hydroxyestrone, with 2-hydroxyestrone as the major metabolite. CYP1A2 had the highest activity for the 2-hydroxylation of both 17beta-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 16alpha- and 16beta-hydroxyestrogens were also formed. The ratio of 4- to 2-hydroxylation of 17beta-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 17beta-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 16alpha-hydroxylation of estrone, but not 17beta-estradiol. CYP4A11 had little catalytic activity for the metabolism of 17beta-estradiol and estrone. In conclusion, many human CYP isoforms are involved in the oxidative metabolism of 17beta-estradiol and estrone, with a varying degree of catalytic activity and distinct regioselectivity. |
| Databáze: | OpenAIRE |
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