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Human Cytochrome P450 3A7 Has a Distinct High Catalytic Activity for the 16-Hydroxylation of Estrone but not 17ß-Estradiol¹

Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208 [A. J. L., B. T. Z.], and Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers–The State University of New Jersey, Piscataway, New Jersey 08854 [A. H. C.]

Like catechol estrogens, 16-hydroxylated estrogens are hormonally active, chemically reactive, and potentially mutagenic. We report here our novel findings that human CYP3A7 has a distinct high catalytic activity for the NADPH-dependent 16-hydroxylation of estrone (E₁; at 10 nM to 200 µM substrate concentrations) but not for the 16-hydroxylation of 17ß-estradiol (E₂). At a physiologically relevant low substrate concentration (10 nM), CYP3A7 had a strong catalytic activity for the 16-hydroxylation of E₁, and the ratio of its 16-hydroxylation to 2-hydroxylation was 107%. In addition to 16-hydroxylation, CYP3A7 also had catalytic activity for the 2-, 4-, 6ß-, and 16ß-hydroxylation of E₁. However, when E₂ was the substrate, CYP3A7 had only very weak catalytic activity for its 16-hydroxylation (<6% of E₁ 16-hydroxylation), and the ratio of its 16-hydroxylation to 2-hydroxylation was 10–33%. Enzyme kinetic analysis showed that the maximal velocity and substrate-binding affinity (1/K_m) for CYP3A7-mediated 16-hydroxylation of E₁ were both 10 times higher than those for E₂, thereby giving the maximal velocity:K_m ratio of >100 times higher for the 16-hydroxylation of E₁ than for E₂. Given the recent findings that human CYP3A7 is a polymorphic isoform also expressed in adult liver and certain extrahepatic tissues (in addition to fetal tissues), our data raise the possibility that CYP3A7 may be an important catalyst for the local and/or systemic formation of the procarcinogenic 16-hydroxyestrone in women.

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